International Journal of Pharmacy

S. Jeganath. et al. / International Journal of Pharmacy, 2(1), 2012, 6-11.
International Journal of Pharmacy

www.ijpjournal.org
e-ISSN: 2249 7684
Print ISSN: 2249 7692
TECHNOLOGICAL DEVELOPMENT AND STABILITY STUDY OF

DIVALPROEX SODIUM EXTENDED RELEASE TABLETS
S. Jeganath1*, K. Senthil kumaran1, V. Ashlin Viji2, K. Sheeja Devi3
Department of pharmaceutics, K.K. College of pharmacy, Chennai, Tamilnadu, India.
Department of Pharmaceutics, Periyar College of Pharmaceutical sciences, Trichy, Tamilnadu, India.
Department of Pharmaceutical chemistry, KMCH college of Pharmacy, Coimbatore, Tamilnadu, India.
ABSTRACT
The behavior of different technological variants of extended release tablets of divalproex Sodium (960mg) obtained by
direct compression technique. The extended time and the percentage of the dissolved drug showed a significant dependence of
the polymers ratios present in formulae. The physical and chemical properties of tablets were assessed during 3 months
(accelerated stability), respectively. From the formulae selected it was possible to obtain granulates and tablets with
organoleptic, physiochemical and technological properties, demonstrating the feasibility of the process of fabrication of this
product. Results showed the good stability in the extended release divalproex Sodium tablets selected. The in vitro dissolution
hasn't significant differences, thus, neither the time elapsed nor the composition of formula influenced on the percentages of
dissolved drug. The assessment demonstrated significant differences, however, assessed formulae fulfilled with official
pharmaceutical specifications during 3 months.
Keywords:-Divalproex sodium, Hydroxyl Propyl Methyl Cellulose, Extended release, Direct compression technique, Stability
studies.
INTRODUCTION
The terms of sustained or extended release,
prolonged release, and controlled release, as applied to
drug formulations, have the meanings ascribed to them in
Remingtons pharmaceutical Sciences, Sustained or
extended release [1] drugs systems include any drug
delivery system which achieves the slow release of drug
over an extended period of time, and include both
prolonged and controlled release system [2,3]. If such a
sustained release system is effective in maintaining
substantially constant drug level in the blood or target. It is
considered a prolonged released system. The sustained or
extended release is explained below a figure:Careful selection of the excipients, components of
all pharmaceutical products, is essential for the
development of stable and effective dosage forms

[4,5]. For an efficient development of stable formulations a
two-step procedure should be recommended. First, design
and optimization of pharmaceutical formulation with
appropriate technological properties andminimum trials.
For that purpose statistical methods have been widely used
[6]. Then, further studies on complete model formulation
with selected excipients should be conducted to verify the
actual stability of the drug in the final dosage form and
identify the most suitable composition in order to
maximize drug stability [7,8]. Stability parameters are
useful for drug formulation and storage conditions, good
practical decisions have to be made on the basis of the
most important parameters like drug dissolution to solid
dosage forms.
Corresponding Author:- S.Jeganath Email: jeganaths@gmail.com
Page | 6
Fig 1. Hypothetical plasma concentration-time profile from single doses of sustained or extended delivery
formulations
MATERIALS AND METHODS

MATERIALS
Divalproex sodium was obtained as a gift sample
from (Sun pharma.Ltd, Mumbai.). HPMC K-100M and
HPMC K4M was obtained as a gift sample from Dow
international. Ltd, Mumbai, and Colorcon Ltd., Asia.
Micro crystalline cellulose and Magnesium Stearate from
LobaChem (Mumbai, India). All other chemicals and
ingredients were used for study are of Analytical grade.
METHODS
Preparation of divalproex Sodium extended release
tablets
Sift Divalproex sodium through 20mesh sieves,
Sift HPMC K-100M, HPMC K4M, PVP-K30, Avicel
pH102, Starch, Lactose DCL-21 Through 40mesh sieve,
dry Mix Divalproex sodium HPMC K4M, HPMC K4M,
PVP-K30, Avicel pH102, Starch, Lactose DCL-21 in a
planetary mixer for 30 minutes. Sift Talc, Aerosil, and
Magnesium stearate through 60 mesh sieve and add to step
2and mix it for 3 minutes. Compress the lubricated blend
Using (D-Tooling) 19.2 x 8.9 mm oblong shaped punches.
For film Coating, Dissolve required amount of HPMC
15cps in IPA & Methylene chloride solution. Add Talc,
Titanium dioxide, Iron oxide yellow to step 1 and mix it in
a colloidal mill for 10 minutes. Polyethylene glycol to step
2 and mix it for 5 minutes. Filter the solution through 200
mesh nylon cloth. Use this coating solution to coat the core
tablets in a Neo-cota coating pan. Spray gun pressure
should be held at an angle of approximately 60C to the

surface of the tablet bed and 30cms away from bed [9,10].
EVALUATION PAPRAMETERS
STABILITY STUDIES
Stability conditions
Once the final formula is arrived at, and then the
stability batches are prepared where three batches of the
same formula are prepared and packed in Alu strip, Alu
Blister, amber PVDC 60, and HDPE. These packed
samples are stored in three conditions.
25C and 60%RH

30C and 65% RH
40C and 75% RH
For periods of 1, 2,3,6,9,12,18,24 and 36 months
as may be the case applicable. These are in line with the
ICH guidelines The optimized formulations of T 7,T8 and
was chosen for stability studies, Tablets were packed in
Alu-Alu Blister and kept for 90 days at 400 C /75% RH and
300 C /65% RH in a stability chamber (New tronic walk in
humidity chamber, India). The tablets were evaluated
interval of 1, 2, 3 months analysis as per in-house
specification.
RESULTS AND DISCUSSION
The Aim of the present study was to formulate the
Extended Release Tablet of Divalproex Sodium using
different viscosity concentration of hydrophilic polymer
Page | 7
like Hydroxyl Propyl Methyl Cellulose K4M and Hydroxyl

Propyl Methyl Cellulose K100M with diluents like
microcrystalline cellulose, Maize starch by direct
compression method.
with the in-house specification release profile hence was

chosen T5 batch taken for their stability studies. The
stability studies were performed on selected formulations
i.e. T5 at 300C 20C / 60% 5% RH (Real time stability),
and 400C 20C / 75% 5% RH (accelerated stability), for
3months. At the interval of 1 month the formulations were
checked for physical appearance, drug content, hardness
and dissolution profile etc. There was no physical change
has been observed in the formulations at stability
conditions and also there was no significant change has
been observed in drug content, Hardness and friability
dissolution profile of the selected formulations at stability
conditions as shown in Table No.3. So T 5 formulations
were found to be stable.
The prepared formulation (ER tablets) was

evaluated precompression and invitro studies. The results
are showed good with in IP specification limits. The in
vitro dissolution studies were performed for the T 1, T2, T3,
T4, T5, and T6 formulations. In this formulation T 5 complies
as per in-house specification with marketed sample.
STABILITY STUDIES
The In-vitro release of formulation T5 complies
Comparative Release profile of fabricated Divalproex sodium ER Trial No.5 with Market sample as shown in Fig No.2.
100
90
80
% Drug release
70
60
50
40
30
20
10
0
0
10
15
20
25
30
Time in hours
Page | 8
Table 1. Formulation of Divalproex Sodium Extended Release Tablets

S.No
Ingredients
T1 (mg)
T2( mg)
T3 (mg)
T4 (mg)
T5 (mg)
T6 (mg)
T7 (mg)
T8 (mg)
Divalproex
sodium
549.00
549.00
549.00
549.00
549.00
549.00
549.00
549.00
HPMC
K100M
75.00
(8%)
56.00
(6%)
56.00
(6%)
47.00
(5%)
40.00
(4%)
18.50
(2%)
40.00
(4%)
40.00
(4%)
HPMC K4M
47.00
(5%)
37.00
(4%)
28.20
(3%)
18.80
(2%)
25.00
(2.5%)
14.0
(1.5%)
25.00
(2.5%)
25.00
(2.5%)
Povidone
(K30)
25.00
25.00
25.00
25.00
25.00
25.00
25.00
25.00
Avicel pH 102
14.00
43.00
51.80
70.2
71.00
103.50
71.00
71.00
Starch
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
Lactose DCL
21
80.00
80.00
80.00
80.00
80.00
80.00
80.00
80.00
Talc
30.00
30.00
30.00
30.00
30.00
30.00
30.00
30.00
Magnesium
stearate
15.00
15.00
15.00
15.00
15.00
15.00
15.00
15.00
10
Aerosil
5.00
5.00
5.00
5.00
5.00
5.00
5.00
5.00
11
Target
Weight
940.001%
940.001
%
940.001%
940.001%
940.001%
940.001% 940.00 1%
940.00 1%
Page | 9
Core tablets are film coated with following ingredients listed in Table No.2
Table 2. Coating Formula
Ingredients
HPMC 15CPs
Titanium dioxide
Talc
Iron oxide yellow
Propylene glycol
Isopropyl alcohol
Methylene chloride
Target weight of a coated tablet
Quantity
12.00
3.90
2.40
0.10
1.6
q.s
q.s
960.001%
Table 3. Comparative drug Release Profile of Trial No.5 with Market Sample (DIVALPRID-OD Tablet)
S.No
Medium
1
2
3
4
Acid(1.1N Hcl)
Time (in hours)
Cumulative % drug release

Trial no-5
Marketed Sample
8.1
6.8
31.9
31.4
79.5
81.9
91.3
92.7
1
3
12
24
Phosphate Buffer
(pH 6.8)
Table 4. Stability data for Divalproex Sodium ER Tablets T5

Accelerated Stability- 400C/70%RH
Real Time Stability-300C/65%RH
S.No
1
Parameter
Appearance
3Month
300C/65%RH
3Month
960.2mg
960.4mg
960.0mg
957.0mg
951.0mg
6.0
5.8
5.0
5.2
5.2
6.9%
24.3%
69.8%
89.9%
8.2%
32.1%
75.5%
85.6%
12.3%
30.6%
70.95%
86.6%
9.2%
22.1%
73.8%
88.5%
9.9%
23.7%
74.9%
86.3%
98.6%
99.40%
99.75%
99.21%
99.8%
Initial
Light yellow colored,

oblong shaped film
coated tablets
950-970mg(Taget
weight-960mg)
Average
weight
Hardness of
3
4.00 to 8.00 kg/cm2
tablets
Dissolution
NMT15%
1st Hour
Between20%to45%
rd
4
3 Hour
NLT 60%
12th Hour
Not
less than 80%
24th Hour
Assay
Each film
coated ER
90.0% to 110.0% (4905.
tablet contain
550.0mg)
divalproex
sodium
- indicate complies as per in-house specification
2
1Month
400c/70%RH
2Month
Limits
Page | 10
CONCLUSION
The Conclusion of this work was to develop a
stable solid dosage form of extended release tablets of
Divalprex sodium for the treatment of epilepsy bipolar
disorder, and migraine headache. In the present study
extended release of Divalproex sodium tablet was prepared
by using direct compression technique. Different
formulations were made by using two rate retaining
polymer like HPMCK 100M and HPMC K4M combined

with directly compressible grade diluents like
Microcrystalline cellulose pH102, Starch, Lactose DCL21
and finally tablet was made film coated. From the above
study the formula used for T5 formulation was concluded
as an optimized formula due to its good in vitro release
characteristics and stability studies.
REFERENCES
1. Remingtons pharmaceutical Sciences and practice of pharmacy 18th ed. Mack Publication, 2, 1996, 1677.
2. Theodore JR, Mansdorf SY. Controlled release drug delivery system. New York: Marcel Dekker, 1, 1983, 1-5.
3. Donald LW. Bioploymeric controlled release system. USA: CRS Press Inc, 1, 1984, 253-65.
4. Garnet EP, Baley GJ, McCurdy VE, Banker GS. Pharmaceutical dosage forms: Tablets. New York: Marcel Dekker, 1,
1989, 85-7.
5. Serajuddin ATM, Thakur AB, Ghosal RN, Fakes MG, Ranadive SA, Morris KH, et al. Selection of solid dosage form
composition through drug-excipient compatibility testing. J Pharm Sci, 88, 1999, 696-704.
6. Furlanetto S, Cirri M, Maestrelli F, Corti G, Mura P. Study of formulation variables influencing the drug release rate from
matrix tablets by experimental design. Eur J Pharm Biopharm, 62, 2006, 77-84.
7. Fernndez EG, Fernndez Cervera M, Oliveira RT, Bermdez B, Prez I, Morn Y, et al. Diseos de experimentos en
tecnologa y control de los medicamentos. Lat Am J Pharm, 27(2), 2008, 286-96.
8. Mura P, Furnaletto S, Cirri M, Maestrelli F, Marras AM, Pinzauti S. Optimization of glybenclamide tablet composition
through the combined use of differential scanning calorimetry and D-optimal mixture experimental design. J Pharm
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extended-release matrix tablets using response surface methodology. Int J Pharm, 289, 2005, 87-95.
10. Manon Thibault, Warren TB, Jean-Marc Saint-H, Rafik Z, Kenneth W. Sommerville .Divalproex extended-release versus
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S. Jeganath. et al. / International Journal of Pharmacy, 2(1), 2012, 6-11.