145

Fasiuddin Arif Mohammed. et al. / International Journal of Biological & Pharmaceutical Research. 2012; 3(1): 145-153.

ISSN 0976 - 3651

2229 - 7480

International Journal of Biological

&
Pharmaceutical Research
Journal homepage: www.ijbpr.com IJBPR
FORMULATION AND EVALUATION OF CARBAMAZEPINE
EXTENDED RELEASE TABLETS USP 200MG
Fasiuddin Arif Mohammed*1, A.Arunachalam2, G.Venkatarami Reddy3, V.Pallavi3,
SK.Moulali4, T.V.Tulasi Rama Raju4

*,1Dr.Reddy’s Laboratories Limited, Bachupally, Hyderabad, Andhra Pradesh, India.

2
Department of Pharmaceutics, A.M.Reddy Memorial College of Pharmacy, Narasaraopet, Guntur, Andhra Pradesh, India.
3
Department of Pharmaceutics, ASN Pharmacy College, Tenali, Andhra Pradesh, India.
4
A.M.Reddy Memorial College of Pharmacy, Narasaraopet, Guntur, Andhra Pradesh, India.

ABSTRACT
The objective of this research work was to formulate and evaluate the extended release tablets containing 200mg of
Carbamazepine. Different excipients were tested for their compatibility with Carbamazepine, which revealed that there is no
physical and chemical interaction occurred. Extended release tablets were formulated by Wet Granulation method incorporating
HPMC K4M, a hydrophilic polymer, Dicalcium phosphate (Anhydrous) as diluent, Povidone (K-30) as Binder, Colloidal
silicon dioxide (Aerosil-200) as Glidant, Hydrogenated Castor Oil (Boricin Pharma) and Talc as lubricants. Dissolution profiles
were studied in Purified water as dissolution medium (900ml). The drug release were estimated at 3, 6, 12 and 24 hours by
Ultra violet – Visible spectrophotometer (UV 1601, Shimadzu), at 284 nm. The influence of variables like polymer type, drug:
polymer ratio on Carbamazepine profile release was studied. The release mechanisms of Carbamazepine extended release
tablets were evaluated. The thickness, hardness, friability, weight variation and drug content of the formulated extended release
tablets were evaluated. Based on the evaluation results, T9 (10% Methocel K4M) formulation was selected as the best
formulation, reproducibility trials were taken and the results were found to be satisfactory.

Key Words: Carbamazepine, Hydroxy Propyl Methyl Cellulose (HPMC K4M), Wet Granulation method, Extended release
drug delivery and Evaluation.

INTRODUCTION
Oral administration of drugs has been the most
common and preferred route for delivery of most
therapeutic agents. It remains the preferred route of
administration investigated in the discovery and
development of new drug candidates and formulations. The
Corresponding Author
Fasiuddin Arif Mohammed
Email: md.arif150@gmail.com
popularity of the oral route is attributed to patient
acceptance, ease of administration, accurate dosing, cost-
effective manufacturing methods, and generally improved
shelf-life of the product. For many drugs and therapeutic
indications, conventional multiple dosing of immediate
release formulations provides satisfactory clinical
performance with an appropriate balance of efficacy and
safety. The rationale for development of an extended-
release formulation of a drug is to enhance its therapeutic
benefits, minimizing its side effects while improving the
management of the diseased condition (Lloyd NS et al.,
1999).

Fasiuddin Arif Mohammed. et al. / International Journal of Biological & Pharmaceutical Research. 2012; 3(1): 145-153.
Epilepsy is a common chronic neurological
disorder characterized by recurrent unprovoked seizures.
These seizures are transient signs and/or symptoms due to
abnormal, excessive or synchronous neuronal activity in
the brain. Epilepsy is usually controlled, but not cured,
with medication, although surgery may be considered in
difficult cases (Cascino GD et al., 1994; Jerome Engel et
al., 2006).
Carbamazepine is an anti convulsant and specific
analgesic for trigeminal neuralgia that reduces
polysynaptic responses and blocks post titanic potentiation.
Carbamazepine is effective in partial and generalized
convulsions and in mixed types. It is not effective in petit–
mal seizures. It reduces (or) abolishes pain in trigeminal
neuralgia and glosso pharyngeal neuralgia. Carbamazepine
extended release tablets are used to treat episodes of mania
(or) mixed episodes i.e., symptoms of mania and
depression that happen at the same time, in patients with
bipolar disorder. It works by reducing abnormal excitement
in the brain (Gonzalez, Frank J et al., 2006; Bertilsson L et
al., 1978).
The extended release drug products designed to
reduce the frequency of dosing by modifying the rate of
drug absorption have been available for many years. Early
modified-release products were often
intramuscular/subcutaneous injections of suspensions of
insoluble drug complexes, e.g. procaine penicillin,
protamine zinc insulin, insulin zinc suspensions or
injections of the drug in oil, e.g. Fluphenazine decanoate.
In conventional dosage forms, which include Capsules,
solutions, suspensions and tablets, the drug is released by
dissolution or diffusion. The resulting pattern of drug
concentration in plasma can vary widely and may cause
inconsistent and undesired clinical effects. The high peak
blood concentration reached soon after administration may
result in adverse effects. With Controlled release products
the precise rate, extent or timing of drug entry into the
blood stream is predetermined or achieved with an integral
drug – specific composition, structure or mechanism
(Collett J et al., 1988; Alderman DA et.al., 2002).
MATERIALS AND METHODS
MATERIALS
Carbamazepine was obtained as a gift sample
from M/S Sun Pharma Ltd., India. Methocel K4M was
obtained as a gift sample from Colorcon Ltd., India.
HPMC 5 CPS and Povidone (k-30) were obtained as a gift
samples from Natco Pharma Ltd, India. Dicalcium
phosphate (Anhydrous) was obtained as a gift sample from
Enar Chemicals Pvt Ltd., India. Povidone Other chemicals
and solvents were used of AR grade.
METHODS
146
MANUFACTURING PROCESS
The Manufacturing procedure to formulate
Carbamazepine extended release tablets USP 200mg
consists of the following steps: (Kuksala et al., 2006;
Owen et al., 2006)
1. SIFTING: Sift Carbamazepine through #80 mesh, Sift
Methocel K4M,Dicalcium phosphate (Anhydrous),
HPMC 5CPs through #40mesh.
2. DRY MIXING :Load the materials of stage-1 into
planetary mixer and mix for 20 mins at slow speed.
3. BINDERPREPARATION :Dissolve Povidone (K-
30) in a (1:1) mixture of Isopropyl Alcoholand
Methylene chloride.
4. GRANULATION:Add slowly binder solution of
stage – 3 to stage – 2 and mix for 5mins at slow speed.
After complete addition of binder solution, mix until
to get granules.
5. DRYING :Load the wet granules of stage – 4 into
Tray drier, dry untill the moisture content of granules
is not more than 1.0%
6. SIZING :Mill the dried granules of stage – 5 through
Multimill with 1.5 mm screen and sift through # 20
mesh sieve. Retained granules mill through Multimill
and sift through # 20 mesh.
7. LUBRICATION :Sift Colloidal silicon dioxide,
Hydrogenated castor oil (Boricin pharma) and talc
through # 40 mesh, Load the granules of stage – 6 and
lubricants into Octogonal blender. Mix for 3 minutes
at slow speed.
8. COMPRESSION :Compress the lubricated blend in a
cadmach Compression machine with 9.5mm flat
punches with break line on one surface.
EVALUATION PARAMETERS AND PROCEDURES
DRUG-EXCIPIENT COMPATABILITY STUDIES
Pre formulation testing is an investigation of
physical and chemical properties of drug substances alone
and when combined with excipients. It is the first step in
the rational development of dosage form (Ifat Katzhendler
et al., 1988).
The active ingredient (Carbamazepine) with
various excipients in 1:1 and 1:10 ratio were taken in glass
vial and kept at various conditions ( 400C/75%RH and
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Fasiuddin Arif Mohammed. et al. / International Journal of Biological & Pharmaceutical Research. 2012; 3(1): 145-153.

600C/80%RH) in stability chamber (Newtronic walkin
Humidity chamber, India).The study is carried out in open
and closed glass vials for a period of a month. The
samples were withdrawn at intervals of 7, 15 and 30 days
and characteristic like colour change, water content and
related substances was recorded. Finally the compatible
mixtures were selected for formulation (Kumar et al.,
2010).
Evaluation of granules
DENSITY (g/ml)
Granule density, True Density, Bulk density may
influence compressibility, tablet porosity, flow property,
dissolution and other properties. Higher compression load
is required in case of dense and hard granules which in turn
increase the tablet disintegration and drug dissolution time.
Density is usually determined by Pycnometer.
Bulk density
Procedure
Weighed quantity of Carbamazepine granules was
transferred into a 50 ml measuring cylinder without
tapping. During transfer the volume occupied by granules
was measured. Bulk density was measured by using
formula.
Pi = m/Vo
Where,
m : Mass of the blend
Vo: Untapped Volume
Tapped Density
Procedure
Weighed quantity of Carbamazepine granules was
taken into a graduated cylinder, volume occupied by
granules was noted down. Then cylinder was subjected to
500/ 750 and 1250 taps in tapped density tester (Electro
Lab USP II) According to USP , the blend was subjected
for 500 taps the % Volume variation was calculated by
following formula.
Where, Pt = m/Vi
m: Mass of the blend
Vi : Tapped Volume
COMPRESSIBILITY INDEX: (CI)
Compressibility is the ability of powder to
decrease in volume under pressure. Compressibility is a
measure that obtained from density determination.
to 500/ 750 and 1250 taps in tapped density tester (Electro
Lab USP II) the difference between two tabs should be less
than 2%. The percentage of compressibility Index is
calculated by using formula (James L et al., 1985;
Carri.R.L et al., 1965)
CI=Vo-Vi/V*100
Where, Vo : Untapped density
Vi: Tapped density
HAUSNER’S RATIO
It is measurement of frictional resistance of the
drug. The Ideal range should be 1.2 -1.5. It was determined
by the ratio of tapped density to bulk density.
Hausner’s Ratio = Vo/Vi
Where, Vo : Untapped density
Vi : Tapped density
ANGLE OF REPOSE
Angle of Repose (Ф) is the maximum angle
between the surface of a pile of powder and horizontal
plane. It is usually determined by fixed funnel method and
is the measure the flowability of powder /granules.
Procedure
Carbamazepine granules were passed through a
funnel kept at a height of 2 cm from the base. The granules
were passed till it forms heap and touches the tip of the
funnel. The radius was measured and angle of repose was
calculated by using the formula.
Ф = tan –1(h/r) (or) Ф = tan –1(height /0.5 Base)
Where,
h : Height of the heap of pile
r : Radius of base of pile
WATER CONTENT
Water content (By KF)
Determine the water content of the sample by
using suitable Karl Fischer titrator. Transfer about 200ml
of the powdered tablet into the titration vessel and titer the
solution. Calculate the water content of the test sample by
using the following equation.
Volume of K.F.Reagent X K.F Factor
Water content (%) = -------------------------------------X100
Weight of the sample in mg
EVALUATION OF TABLETS

Procedure Thickness or dimension test

Weighed quantity of Carbamazepine granules was The thickness of the tablets was measured using
transferred to 50 ml graduated cylinder, volume occupied Digital Vernier Caliper. It is expressed in mm. (Values are
by granules was noted down. Then cylinder was subjected given in Table 7)

Fasiuddin Arif Mohammed. et al. / International Journal of Biological & Pharmaceutical Research. 2012; 3(1): 145-153.
Hardness test
Hardness indicates the ability of a tablet to
withstand mechanical shocks while handling. The hardness
of tablets was determined by using Monsanto hardness
tester. It is expressed in kg/cm2. Three tablets were
randomly picked and hardness of tablets was determined.
(Values are given in Table 7)
Limits: 4 – 10 kg/cm2
Friability test
Friability of the tablets is determined by using Roche’s
friabilator. It is expressed in %. Ten tablets were initially
weighed and transferred to friabilator. The friabilator is
operated at 25 Rpm for 4 min or run upto100 revolutions,
the tablets are weighed again. The % friability of tablets
was then calculated. (Values are given in Table 7)
Limits: The Friability of tablet should not be exceed 1%
Initial wt – Final wt
F = _________________ X 100
Initial wt
Weight variation test
Ten tablets were selected randomly from each batch
and weighed individually to check for weight variation. A
little weight variation is allowed by U.S pharmacopeia.
The following % weight variation is allowed (Ikinci G et
al., 1999; Vidyadhara S et al., 2003). (Values are given in
Table 5)
CONTENT OF UNIFORMITY
Standard preparation
Weigh accurately about 0.1g of Carbamazepine
WS in to a 50ml volumetric flask, add 30ml of methanol,
shake and sonicate to dissolve the content, makeup the
volume with methanol. Filter the solution through
membrane filter. Pipette out 5 ml of the above solution in
to a 100 ml volumetric flask and makeup the volume with
methanol. Further, pipette out 5ml of the above solution in
to a 50ml volumetric flask and makeup the volume with
methanol.
Sample preparation
Randomly select 10 tablets. Finally powder one
tablet and transfer quantitatively the powdered tablet into a
100ml volumetric flask. Add 70ml of methanol shake by
mechanical means for 60 minutes; sonicate for 15 minutes
and makeup the volume with methanol. Allow to stand for
10 to 15 minutes, and then filter the portion of the
supernatant solution through a membrane filter. Pipette out
5 ml of the above solution into a 100 ml volumetric flask
and makeup the volume with methanol. Further, pipette out
5 ml of the above solution into a 50 ml volumetric flask
and make up the volume with methanol.
148
PROCEDURE
Measure the absorbance of the Standard preparation
and sample preparation using suitable UV–Visible
spectrophotometer at about 284nm using methanol as
blank. Calculate the release of Carbamazepine in
percentage with respect to the label claim by using the
following expression.
AT X WS X 5 X 5 X 100 X 100 X 50 X P 100
_______________________________________ X 1000 X__________
AS X 50 X 100 X 50 X 1 X 5 X 5 X 100 200
= % of Carbamazepine
Where AS is the absorbance of the
Carbamazepine in Standard preparation and AT is the
absorbance of the Carbamazepine in Sample preparation,
WS is Weight of Carbamazepine WS taken for Standard
preparation in g and P is percentage purity of
Carbamazepine WS on as such basis.
Repeat the above procedure for further 9 tablets
and calculates the content of Carbamazepine in percentage
with respect to label claim and finds the average value for
the 10 tablets tested. Calculate the limit for uniformity of
content.
In vitro dissolution studies
Apparatus : Dissolution Apparatus 1 USP (basket)
Speed : 100 rpm
Medium : water; 900ml
Temperature : 37 0 c + 0.5 0c
Time : 3rd, 6th, 12th and 24th hours
Procedure
In-vitro dissolution testing of Carbamazepine
extended release tablets was carried out by using IP/USP
dissolution apparatus (basket type and apparatus-1) with
900ml of Distilled water as dissolution medium, which is
maintained at 37±0.50C. The basket was rotated at a fixed
rpm of 100 at specified interval time, required volume of
sample (1ml) was pipetted or withdraws out and diluted to
10ml in volumetric flask with Distilled water, then finally,
the absorbance of the sample solution in each flask was
measured at 284 nm against Distilled water used as blank.
An amount of drug release and % drug release was
calculated by using below formula:
i) Amount of drug release =
Concentration (µg/ml) × Dilution factor (ml) × Bath volume (ml)
1000
ii) % Drug release = Amount of drug release × 100
Labelled claim
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RESULTS AND DISCUSSION

Table 1. Comparative formula of Carbamazepine extended release tablets USP 200 mg

Quantity/Tablet (mg)
Ingredients T-1 T-2 T-3 T-4 T-5 T-6 T-7 T-8 T-9 T-10 T-11 T-12
Carbamazepine 201.59 201.59 201.59 201.59 201.59 201.59 201.59 201.59 201.59 201.59 201.59 201.59
Hydroxy Propyl
Methyl Cellulose 97.50 89.38 81.25 73.12 65.00 56.87 48.75 40.63 32.500 32.50 32.50 32.50
(Methocel K4M)
Hydroxy Propyl
Methyl Cellulose _ _ _ _ _ _ _ _ 6.250 _ _ _
(HPMC 5CPs)
Dibasic calcium
phosphate 3.91 12.03 20.16 28.29 36.41 44.54 52.66 60.78 52.660 68.91 68.91 68.91
(Anhydrous)
Povidone (K-30) 10.00 10.00 10.00 10.00 10.000 10.00 10.00 10.00 10.00 10.000 10.000 10.000
Isopropyl Alcohol q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s
Methylene chloride q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s
Hydrogenated
castor oil 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.000 5.000 5.000
(Boricin pharma)
Colloidal silicon
dioxide 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2.000 2.000 2.000
(Aerosil – 200)
Talc 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.000 5.000 5.000
Average Weight 325.00 325.00 325.00 325.00 325.00 325.00 325.00 325.00 325.00 325.00 325.00 325.00

Table 2. Compressibility Index

Compressibility Index Flow characters
< 10 Excellent
11 –15 Good
16 – 20 Fair
21 25 Passable
26 – 31 Poor
32 –37 Very Poor
> 38 Very Very Poor

Table 3. Hausner’s ratio

Flow characters Hausner’s ratio

Excellent 1.00 – 1.11
Good 1.12 – 1.18
Fair 1.19 – 1.25
Passable 1.26 – 1.34
Poor 1.35 –1.45
Very Poor 1.46 – 1.59
Very Very Poor > 1.60
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Table 4. Flow Properties and Corresponding Angle of Repose

Flow Properties Angle of Repose (Degrees)

Excellent 25 –30
Good 31 –35
Fair – aid 36 –40
Passable 41 –45
Poor 46 – 55
Very Poor 56- 65
Very Very Poor > 66

Table 5. Weight variation test

S.no Average weight of tablets % variation

1 130 or less ± 10
2 >130- <324mg ± 7.5
3 >324 mg ±5

Table 6. Drug Excipient Compatibility for Carbamazepine

Conditions
Initial
400C/75%RH 600C/90%RH
S.No Drug+ Excipients Parameter value of
2 4 2 4
parameters
Week Week Week week
Any colour No colour No colour No colour No colour No colour
1 Carbamazepine
change change change change change change
Carbamazepine + Dibasic
Any colour No colour No colour No colour No colour No colour
2 calcium phosphate
change change change change change change
(Anhydrous)
Carbamazepine+ HPMC Any colour No colour No colour No colour No colour No colour
3
K4M change change change change change change
Carbamazepine+ HPMC 5 Any colour No colour No colour No colour No colour No colour
4
CPs change change change change change change
Carbamazepine+ Povidone Any colour No colour No colour No colour No colour No colour
5
(K-30) change change change change change change
Carbamazepine + Iso
Any colour No colour No colour No colour No colour No colour
6 propyl alcohol &
change change change change change change
methylene chloride
Carbamazepine + colloidal
Any colour No colour No colour No colour No colour No colour
7 silicon dioxide (Aerosil-
change change change change change change
200)
Any colour No colour No colour No colour No colour No colour
8 carbamazepine+Talc
change change change change change change
Carbamazepine+
Any colour No colour No colour No colour No colour No colour
9 hydrogenated castor oil
change change change change change change
(Boricin pharma)
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Table 7. Evaluation of granules of all formulations

Bulk density Tap density Hausner’s Compressibility Angle of repose Moisture

S. No Formulation
(g/cm3) (g/cm3) ratio Index (%) (0 ) Content (%)
1 T1 0.57 0.65 1.12 11.4 31.2º 0.81
2 T2 0.56 0.64 1.14 12.5 28.6º 0.79
3 T3 0.56 0.63 1.13 12.5 30.2º 1.02
4 T4 0.59 0.69 1.17 14.7 27.3º 1.06
5 T5 0.63 0.76 1.19 16.2 25.3º 0.97
6 T6 0.64 0.78 1.21 17.8 28.4º 0.84
7 T7 0.65 0.75 1.19 16.4 26.9º 0.96
8 T8 0.64 0.75 1.19 16.2 24.8º 0.82
9 T9 0.54 0.62 1.14 12.8 25.6º 0.93
10 T10 0.53 0.60 1.13 11.7 26.4º 1.09
11 T11 0.63 0.71 1.16 12.5 25.7º 1.06
12 T12 0.61 0.68 1.14 12.6 24.9º 0.92

Table 8. EVAULATION OF CARBAMAZEPINE EXTENDED RELEASE TABLETS

S.N TESTS Specification

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12
o.
White, flat,
circular bevel
edged
Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies
uncoated
1 Description
extended
tablets with a
break line on
one surface.
Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies

Complies
Passes for
Identificati
2 carbamazepin
on test
e

321-329mg
Average (Taget
3 325.2 324.9 324.5 325.2 325.5 324.8 325.1 324.6 324.9 323.8 325.4 324.2
weight weight-
325mg)
Thickness
4 3.6-4.0mm 3.80 3.72 3.68 3.89 3.72 3.90 3.84 3.78 3.72 324.6 324.9 323.8
(mm)
Hardness 4.0-8.0 6
5 5 5 6 5 4 5 4 4 5 6 5
(kg/cm2) Kg/cm2
Friability Not more than
6 0.11 0.14 0.12 0.11 0.16 0.15 0.18 0.12 0.15 0.15 0.14
(%w/w) 1.0% 0.08
± 5% from -2.5 -2.5 -2.4 -1.5 -1.9 -1.7 -2.4 -3.1 -2.4 -1.7 -1.5 -2.6
Weight
7 the avearge to to to to + to to to to to to to to
Variation
weight +1.9 +2.1 +1.8 2.8 +2.4 +3.1 +1.8 +2.5 +1.9 +2.7 +2.2 +1.9
Content
8 85 to 115% 95% 98% 97% 98% 98% 99% 97% 96% 98% 98% 99% 98%
Uniformity
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Table 9. INVTRO DISSOLUTION STUDIES

Invtro
S.no Dissolution Specification T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12
(%)
1.
Between 10% 4.3 6.9 7.9 11. 12.1 14.3 15.1 17.5 19.8 28.2 25.9 29.5
3rd hour
to 35% % % % 0% % % % % % % % %
2. Between35% 15.8 16. 18. 20. 23.4 28.5 33.9 35.6 33.5 50.2 48.9 51.3
6th hour
to 65% % 5% 3% 9% % % % % % % % %
3. Between 65% 32.3 39. 43. 48. 53.9 60.5 63.9 68.0 79.9 78.7 73.1 75.6
12th hour
to 90% % 6% 5% 9% % % % % % % % %
4. 58.0 60. 67. 70. 78.1 83.4 96.2 95.6 86.9 93.0 95.4 96.5
24th hour NLT 75%
% 8% 5% 9% % % % % % % % %

Fig 1: Theoretical drug concentration profile following Fig 2. Comparative Release profile of Carbmazepine ER
multiple dosing of a drug as an immediate-release form tablet of Trial 10, Trial-11, Trial-12 with Market sample
every 8 hours and as an extended-release form once every
24 hours.

DISCUSSION found to meet the USP specification when compared with

To match the USP release profile of the drug, the
trial T10 was formulated with 10% of HPMC K4M, where
the release of drug at 3rd hour was found to be 29.5%
respectively, which meets the USP specification limits.
Hence reproducibility trials (T11 and T12) with the same
formula of T9 were taken to confirm whether it meets the
USP specification and it was found to be reproducible. The
release of drug depends not only on the nature of matrix
but also upon the drug polymer concentration. As the
percentage of polymer decreased from 30% to 10% the
release of drug was extended. The extended release tablets
were evaluated as per the USP specification and it was
market sample (Zen retard -INTAS).
CONCLUSION
The present study indicated that the time lag of
compression core coated tablet could be controlled and
suitably modified by formulating the outer shell with Ethyl
Cellulose and Microcrystalline Cellulose or Hydroxy
Propyl Methyl Cellulose. Success of the In vitro drug
release studies recommends the product for further in vivo
studies, which may improve patient compliance. This
formulation can be used for the treatment for epilepsy,
which was formulated by using wet granulation method
consisting of a hydrophilic polymer.
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