ISSN-2321-0966 (Print)

ISSN-2321-0974 (Online)

PHARMAGENE
Vol: 1

Issue: 2

Research Article
www.genesisjournals.org

Optimization of Formulation Variables of Ranolazine Extended-Release

Tablets by 3 2 Full Factorial Design
Shah Pranav*, Naik Bhargavi, Zalak Chandarana
Mali ba Pharmacy College, Bardoli, Gujarat
ABS TRACT
Ranolazine is antianginal drug, approved by US FDA in 2006. It is marketed as extended release tablets (Ranexa 500mg/1gm).
Ranolazine is extensively metabolized in the liver and its absorption is highly variable. The present study was aimed to apply
experimental design in the development and optimization of drug release from extended release matrix tablets of Ranolazine
(antianginal drug) using two factor three level (3 2) full factorial design. The extended release matrix tablets of Ranolazine were
formulated using pH dependent polymer (Eudragit L 100-55), Sodium hydroxide, M CC, HPM C 5 cps and M agnesium stearate.
The amount of independent variables, Eudragit L100-55 (X1) and Sodium Hydroxide (X2) were optimized on the basis of drug
release profiles at 0.5, 4, 12, 24 hours (dependent variables ) of different tablets batches as per 32 full factorial design. Tablets
were prepared by wet granulation technique and evaluated for various physicochemical parameters and in vitro drug release.
Polynomial equations and contour plots derived from the data obtained from 13 batches were used to predict the values of
independent variables and their effect on dependent variables for the formulation of optimized tablets with desired properties.
Optimized formulation from DOE had identical dissolution profile (f2 = 85.95 and f1 = 2.29) with innovators tablet. Stability
studies of optimized batch were conducted at accelerated conditions for three months and tablets were found to be stable. Thus
the study revealed that experimental design could efficiently be applied for optimization of amount of excipients affecting drug
release. Also, it is an economical way of obtaining the maximum amount of information in a short period of time and with the
few experiments.
KEY WORDS : Ranolazine extended release tablet, Experimental design, Full Factorial Design,
Received on 03-05-2013

Modified on 04-06-2013

INTRODUCTION
Oral administration of drugs is strongly preferred because
of its convenience, relatively low production cost and the
high level of patient safety. However there are some
problems associated with the oral drug delivery such as
poor bioavailability, high first pass metabolism, frequent
drug administration etc. Extended-release systems allow
the drug to be released over prolonged time periods. By
extending the release profile of a drug, the frequency of
dosing can be reduced. Extended release can be achieved
using sustained or controlled release dosage forms [1] .
*Address for correspondence:
Dr. Pranav Shah, Professor,
M aliba Pharmacy College, Bardoli, Gujarat, India
Email: pranav.shah@utu.ac.in

Accepted

on

10-06-2013

The oral extended release system shows a typical pattern of

drug release in which the drug concentration can be
maintained in the therapeutic window for a prolonged
period of time (extended release), thereby ensuring
controlled therapeutic action.
Ranolazine is antianginal drug, approved by US FDA in
2006. It is marketed as extended release tablets (Ranexa
500mg/1gm). Ranolazine is extensively metabolized in the
liver and its absorption is highly variable. The apparent
terminal half-life of Ranolazine is 7 hrs. Ranolazine has
relatively high solubility (42.08 mg/ml in 0.1 N HCl) at low
pH in the stomach (pH 1.2 3). The high acid soluble
property of ranolazine results in rapid drug absorption and
clearance, causing large and undesirable fluctuations in

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PHARMAGENE Vol: 1 Issue: 2

plasma concentration of ranolazine and short duration of

action, thus necessitating frequent oral administration for
adequate treatment [2] . The present study was aimed to
develop a matrix tablet using pH-dependent polymer which
is insoluble at low pH and begins to dissolve at about pH >
5. The extended release tablets were formulated using pH
dependent polymer (Eudragit L 100-55), pH independent
binder (HPM C 5 cps) and sodium hydroxide as neutralizing
agent. Sodium hydroxide facilitates the conversion of the
Eudragit L 100-55 into the latex like film formed around
the individual granules which controls the drug release
from the formulation above pH 4.5[3].
Statistical experimental design methodologies are
powerful, efficient and systematic tools in the design of
pharmaceutical dosage forms, allowing a rationalistic study
of the influence of formulation and/or processing
parameters on the selected responses with short experiment
time and improvement in the research and development
work [4-6]. The main objective of the experimental design
strategies is to plan experiments in order to obtain the
maximum information
regarding the considered
experimental domain with the lowest number of
experiments [7]. M oreover, the multi-variant strategy of
experimental design enables the simultaneous evaluation of
the influence of the different variables involved in any
process, being therefore particularly useful when, as in the
case of pre-formulation studies, multiple factors have to be
evaluated simultaneously.
In particular, optimization by means of statistical
experimental design methodologies has been successfully
applied in the development of different kinds of modified
release dosage forms, allowing a quick and efficient
quantification and prediction of the effects of formulation
changes on the considered crucial responses [8-13].
MATERIALS AND METHODS
Materials
Ranolazine was purchased from Virdev Intermediates,
Surat, India. Eudragit L 100-55 was obtained from Evonik
Industries, Germany. M icrocrystalline cellulose was
purchased from FM C Biopolymer, India. HPM C 5cps was
purchased from Colorcon, Goa, India. Sodium hydroxide
was purchased from Cadila Pharmaceutical Ltd., Dholka,
India and M agnesium stearate was purchased from Skant
Healthcare Ltd., M umbai, India.
Experimental Design
Two factor three level (32) full factorial design was
employed for development of ranolazine extended release
matrix tablets. A translation of coded values of independent
variables and experimental design is executed as in table 1.
Independent variables were as follow:
X1 : Amount of Eudragit L 100-55 (mg/tab)
X2 : Amount of Sodium hydroxide (mg/tab)

Dependent variables evaluated were as follows:

Y1 = % drug released in 0.5 hours
Y2 = % drug released in 4 hours
Y3 = % drug released in 12 hours
Y4 = % drug released in 24 hours
Preformulation studies
Preformulation studies were designed to identify
physicochemical properties of Ranolazine and excipients
that may influence formulation design and method of
manufacture.
Table 1: Execution of experimental design and coding
of actual values of independent variables for factorial
design
Batch

Level of Factor
X1
Amount
of
Eudragit L 10055 (mg/tablet)

F1

-1(67)

Level of Factor
X2
Amount
of
Sodium
hydroxide
(mg/tablet)
-1(2.6)

F2

0(83.50)

-1(2.6)

F3

+1(100)

-1(2.6)

F4

-1(67)

0(3.9)

F5

0(83.50)

0(3.9)

F6

+1(100)

0(3.9)

F7

-1(67)

+1(5.2)

F8

0(83.50)

+1(5.2)

F9

+1(100)

+1(5.2)

F10*

0(83.50)

0(3.9)

F11*

0(83.50)

0(3.9)

F12*

0(83.50)

0(3.9)

F13*

0(83.50)

0(3.9)

*Centre point batches

Analytical method development
HPLC method was developed to perform assay and
analysis of dissolution samples of Ranolazine. HPLC
analysis of samples were done using Phenomenex Luna
ODS 250 mm 4.6 mm, 5 microns column with mobile
phase flow rate 1.0 ml/min. M obile phase consist of buffer
pH 7.5 and acetonitrile in the ratio of 40:60. Sample and
standards were dissolved in mobile phase and detected
using UV detector at wavelength 225nm. Fig. 1 shows the
HPLC chromatogram of standard ranolazine (100g/ml)
with retention time of 8.487 minutes.

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PHARMAGENE Vol: 1 Issue: 2

Preparation of tablets
Tablets were prepared by wet granulation technique. Each
batch of tablets (F1 F13) (Table 2) has varied amount of
Eudragit L100-55 and sodium hydroxide. All ingredients
were weighed accurately in required quantity. Ranolazine,
Eudragit L 100-55, Avicel PH 101 and HPM C 5 cps were
sifted through 20# sieve. The materials were mixed in rapid
mixer granulator (RM G) at 75 rpm impeller speed. Binder
solution was prepared by dissolving sodium hydroxide in
sufficient amount of water. Granulation was done in RM G.

The wet mass was dried in FBD at 60C for 20 minutes and
the semi dried mass was passed through 16# and further
dried at the same temperature till LOD value below 2% was
obtained on moisture balance. The dried granules were
passed through 16# sieve. Sized granules were then mixed
with previously sifted magnesium stearate (60#) for 3
minutes. The tablets were compressed with 16.4 8 mm
capsule shaped, standard concave punches with break line
on one side and plain on other side (D tooling).

Table 2: Formulation of tablets batches

Ingredients
Batches
(mg)
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
Ranolazine*
506
506
506
506
506
506
506
506
506
506
506
506
Eudragit
67
83.5
100
67
83.5
100
67
83.5
100
83.5
83.5
83.5
L 100-55
HPM C 5 cps
13
13
13
13
13
13
13
13
13
13
13
13
Sodium
2.6
2.6
2.6
3.9
3.9
3.9
5.2
5.2
5.2
3.9
3.9
3.9
Hydroxide
M agnesium
13
13
13
13
13
13
13
13
13
13
13
13
Stearate
M CC PH 101
58.4
41.9
25.4
57.1
40.6
24.1
55.8
39.3
22.8
40.6
40.6
40.6
Total
tablet 660
660
660
660
660
660
660
660
660
660
660
660
weight
* The potency of Ranolazine was found to be 506 mg for actual dose of 500 mg/tablet; LOD: 0.29%; Assay: 99.1%

F13
506
83.5
13
3.9
13
40.6
660

Figure 1: Chromatogram of standard Ranolazine (100g/mL) (Retention time: 8.487 min)

Assay
Assay of ranolazine was done using HPLC method.
Standard solution was prepared by dissolving 50 mg of
Ranolazine standard in 50 ml mobile phase in volumetric
flask. Tablet powder equivalent to 50 mg of ranolazine was
accurately weighed and transferred into 50 ml volumetric
flask containing 25ml mobile phase (Buffer:Acetonitrile;
40:60), sonicated for 30 minutes, allowed to cool to room
temperature and diluted upto 50ml volume with mobile
phase and mixed. Resulting solution was filtered through
0.45 m PVDF M illipore filter discarding first few ml of
the filtrate. 5.0 ml of clear filtrate was diluted to 50.0 ml
with mobile phase and mixed. 20L of sample and standard
preparation were injected into the column. Chromatogram
was recorded and the response was measured at 225nm.
(Figure: 1) Content of ranolazine per tablet was calculated.

In vitro drug release study (In vitro dissolution study) [14]

In vitro drug release study was performed as per the
following specifications of OGD, 900 ml of 0.1 N HCl
medium at 50 rpm for 24 hours at 370.5 C. A 10 ml of
sample from dissolution medium was withdrawn at
predetermined time intervals (0.5, 2, 4, 8, 12, 20, 24 hours)
and replaced by an equal volume of dissolution medium.
The samples were filtered through 0.45m whatman filter
paper and 5.0 ml of filtrate was diluted to 20.0ml with
dissolution medium. Samples were analyzed using HPLC.
Mechanism of drug release [15-17]
To evaluate the mechanism of drug release from the dosage
form, data for the first 60% of drug release were plotted in
Korsmeyers equation as log cumulative percentage of drug

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

released vs log time, and the exponent n was calculated

from the slope of the straight line.
/ =
Where, M t/M is the fractional solute release, t is the
release time, K is a kinetic constant characteristic of the
drug/ polymer system, and n is an exponent that
characterizes the mechanism of release.

The optimized formulation was subjected to short term

accelerated stability study (40C/75% RH) for the period of
three months as per ICH guidelines. Physical stability was
analyzed by recording the change in appearance, hardness,
friability and chemical stability was analyzed by the change
in the assay and in vitro drug dissolution at the end of three
months.

S tability S tudy
RES ULTS AND DISCUSS ION
Preformulation studies
Ranolazine was found to have very poor compressibility
and flow properties (Carrs index: 36.67, Hausners ratio:
1.5789), hence wet granulation method was opted for better
compression and good flow property for the preparation of
the Ranolazine matrix tablet.

Precompression evaluation of granules exhibited good flow

property (Hausners ratio < 1.25) and good compressibility
(Carrs index < 20%). Post compression evaluation of
tablets such as appearance, dimensions, weight variation,
hardness, friability, and assay were within the
specifications (Table 3).

Table 3: In process quality control of Tablets

Batch

Average
tablet weight
(mg)
n = 20

Hardness
(kg/cm2)
n = 10

F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
F13

662.62.88
659.22.38
663.13.27
661.42.25
658.52.60
660.32.96
662.63.20
659.82.49
658.22.31
662.62.84
659.22.58
663.12.99
661.42.34

17.20.5
17.50.2
17.80.4
17.40.3
17.30.1
17.30.1
17.40.4
17.30.2
17.10.4
17.80.4
17.40.3
17.30.1
17.10.1

Length
(mm)

Dimensions
n=6
Width
(mm)

Thickness
(mm)

16.400.01
16.420.01
16.390.03
16.410.01
16.380.03
16.410.03
16.420.04
16.380.02
16.410.03
16.430.01
16.420.02
16.390.01
16.410.03

8.010.02
8.020.01
8.010.03
7.990.03
7.980.02
8.010.03
7.990.01
8.030.01
8.020.02
8.010.02
8.010.01
8.020.03
7.980.01

5.710.02
5.720.01
5.750.03
5.840.01
5.770.02
5.850.01
5.740.01
5.720.03
5.810.01
5.710.03
5.730.01
5.760.02
5.790.01

% Friability

Assay
n=5

0.064
0.073
0.068
0.066
0.055
0.062
0.059
0.053
0.056
0.073
0.068
0.066
0.055

99.800.10
98.320.20
100.440.23
99.600.33
99.210.19
98.680.22
100.340.30
100.810.36
99.480.20
99.610.33
99.210.19
98.680.22
100.340.30

In vitro drug release study (In vitro dissolution)

In vitro drug release data (Figure 2) showed that the drug
release from all the formulated batches (F1-F13) (n = 3)
was extended upto 24 hours.

Figure 2: Comparative % cumulative drug release

profile of formulations (F1 F13)

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

(c)
(a)

(b)
(d)
Figure 3: Linear correlation plots of dependent variables Y1-Y4 (a-d) between actual and predicted value
Drug Release kinetics
Dissolution data were fitted to zero order, first order,
Higuchi and Korsmeyer kinetic treatment for all the
formulations and different kinetic equations were applied to
interpret the release rate. The formulation with higher
correlation coefficient R2 was found with Higuchis Model
as shown in Table 4 indicating that release from gel
forming system is based on diffusion mechanism for all
formulations. The value of release exponent was more than
0.45 and less than 0.798 indicating non-fickian anomalous
release from all the formulations except F1.
S tatistical Analysis
The two factor three level full f actorial design allowed the
development of mathematical equations, where predicted
results (Y) were assessed as a function of amount of
Eudragit (X1) and amount of Sodium hydroxide (X2) and
calculated as the sum of a constant, two first-order effects
(terms in X1 and X2), one interaction effect (X12) and two
second-order effects (X12 and X22).
The relationship between the two independent variables
(amount of Eudragit L 100-55 and sodium hydroxide) and

the four dependent variables (% drug release at 0.5, 4, 12

and 24 hour) were analyzed using response surface
methodology
Data given in Table 5 depicts that all the models were
significant at the 5% confidence level since P values were
less than 0.05. The large P values for lack of fit (>0.05)
presented in Table 5 (PLOF) show that the F-statistic was
insignificant, implying significant model correlation
between the variables and process responses. Adequate
Precision (AP) values higher than four (Table 5) for all the
responses confirmed that all predicted models can be used
to navigate the design space defined by the full factorial
design. For all the models % CV were not greater than 10%
(Table 5) which indicate that models are reproducible.
M odel equation for the all the variables showed the
negative co-efficient terms for the first order effect,
interaction term and second order effects which indicated
the negative effect on the response with respect to the
independent variable.
Contour Plots and Response S urface Analysis
Figure 4, 5, 6 and 7 (a and b) represents the response
surface plot and contour plot of dependent variables Y1, Y2,

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

Y3 and Y4 respectively. For responses Y1, Y2, Y3 and Y4

drug release decreases rapidly with increase in amount of
one variable while other at low level. This showed that both
the variables (Eudragit L 100-55 and sodium hydroxide)
had prominent negative effect on Y1, Y2, Y3 and Y4. These
results are in confirmation with mechanism.

As the concentration of pH dependent binder increases in

the formulation, there is decrease in the release rate of
ranolazine at pH below 4.5 as enteric coating formed by the
binder was less soluble in acidic pH. Partial neutralizing
agent, sodium hydroxide facilitated the conversion of the
binder into the latex like film formed around the individual
granules which controled the drug release from the
formulation above pH 4.5.

Table 4: Release kinetic data for F1-F13 formulations

Batch no.
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
F13

Zero order
kinetic R2
0.868
0.928
0.951
0.882
0.895
0.972
0.92
0.913
0.99
0.895
0.891
0.898
0.895

Table 5: ANOVA analysis of data

ANOVA results for dependent variables
Y
Mathematical
P value
model
Y1
Y1= +16.01-5.75X 1 <0.0001
-2.56X 2 + 4.49X 124.01X 12-0.74X 22
Y2
Y2=
+43.01- <0.0001
9.07X 1-5.18X 20.67X 12- 6.26X 122.28X 22
Y3
Y3=
+71.73
- <0.0001
9.85X 1-6.10X 20.66X 12 -6.80X 122.4522
Y4
Y4=
+95.20- 0.0206
3.94X 1-3.76X 21.03X 12-3.02X 122.14X 22

First order
kinetic R2
0.888
0.954
0.958
0.885
0.97
0.936
0.959
0.973
0.939
0.972
0.932
0.969
0.964

PLOF

R2

0.4416

Higuchi
kinetic R2
0.984
0.993
0.993
0.991
0.994
0.981
0.997
0.996
0.95
0.994
0.993
0.994
0.994

Korsmeyer Peppas
R2
n
0.976
0.426
0.997
0.452
0.998
0.604
0.997
0.453
0.997
0.465
0.996
0.707
0.998
0.485
0.997
0.499
0.998
0.798
0.997
0.458
0.997
0.458
0.997
0.463
0.997
0.455

Predicted
R2
0.8881

AP

S .D

0.9561

Adjusted
R2
0.9590

1.02

CV
%
7.41

PRES
S
34.30

23.887

0.2642

0.9708

0.9500

0.8094

22.215

1.97

5.05

1777.7
9

0.3627

0.9637

0.9379

0.7897

20.087

2.34

3.47

221.9

0.3641

0.3641

0.6618

0.4945

7.826

2.92

3.14

251.61

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

Figure 4: Response surface plot (a) and Contour plot (b)

for response Y1

Figure 6: Response surface plot (a) and Contour plot (b)

for response Y4

Figure 5: Response surface plot (a) and Contour plot (b)

for response Y2

Figure 7: Response surface plot (a) and Contour plot (b)

for response Y3

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

Optimization
After generating the model polynomial equations to relate
the dependant and independent variables, the process was
optimized for all four responses. The final optimal
experimental parameters were calculated using DesignExpert V8 (8.071).
The optimized batch F14 contains:
Amount of Eudragit L 100-55 (X2) : 80 mg/tab
Amount of NaOH : 3.25 mg/tab
Dissolution profile of Ranexa (innovators formulation) and
optimized formulation F14 were compared using the FDA
recommended similarity factor (f2) (figure 8). The value of
f2 was found to be 85.95 which was above the critical value
(50) indicating an equivalence to the release profile of the
optimum formulation and the innovator profile.

Validation of Response Surface Methodology

Five check point batches were formulated for the validation
of response surface methodology. Actual experimental
responses and predicted responses were then compared to
validate design (Table 6). For all the 5 checkpoint
formulations, the results of the dependent variables were
found to be within limits. For validation of RSM results,
the experimental values of the responses were compared
with the anticipated values and the prediction error was
found to vary between -5.62 and +5.17. These results
demonstrate the reliability of the optimization procedure in
predicting the effect of process variables on the dissolution
behavior of the ranolazine extended release tablet profile.
Table 6: Composition of check point batches and
comparison of experimental and predicted values of
response variables
Check point
Formulations
X1

X2

67.83

2.96

87.62

3.12

71.95

4.81

76.90

4.55

83.50

2.60

Figure 8: Dissolution profile comparison of optimized

batch and innovators product

Figure 9: Overlay plot of optimized batch

S tability study
Stability study of the optimized formulation proved the
physical and chemical integr ity of the developed ranolazine
extended release matrix tablet with no significant change in
the assay and dissolution profile.

Respon
se
Variabl
es
Y1
Y2
Y3
Y4
Y1
Y2
Y3
Y4
Y1
Y2
Y3
Y4
Y1
Y2
Y3
Y4
Y1
Y2
Y3
Y4

Experi
mental
values

Predict
ed
values

19.14
49.63
76.8
98.48
16.37
44.03
70.65
90.57
14.93
43.61
70.99
95.55
15.88
42.42
72.35
96.06
17.56
45.18
76.36
94.30

19.65
48.66
77.62
97.09
15.52
42.57
71.72
95.66
15.67
42.31
70.14
93.29
16.10
42.86
71.04
94.08
17.83
45.90
75.37
96.80

%
predicti
on
Error
-2.70
1.94
-1.07
1.40
5.17
-3.29
-1.51
-5.62
-4.99
2.96
1.19
2.35
-1.41
-1.03
1.79
2.05
-1.53
-1.57
1.31
-2.59

CONCLUS ION
Ranolazine extended release tablets were manufactured by
wet granulation technique. The tablets exhibited drug
release for a period of 24 hours and followed Higuchi
kinetics. The amount of Eudragit L100-55 and Sodium
hydroxide was optimized by 32 full factorial design based
on the drug release. The contour plots represented the
influence of the amount of the independent variable on the

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Optimization of Formulation Variables of Ranolazine Extended-Release Tablets by 32 Full Factor ial Design

drug release. The design was also validated by the check

point batches. The optimized formulation exhibited drug
release similar to the innovator (f2= 85.95). The accelerated
stability studies suggested no significant change in the drug
content, physical properties and drug release.

9.

10.
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