WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Ramulu et al. World Journal of Pharmacy and Pharmaceutical

Sciences SJIF Impact Factor 2.786

Volume 3, Issue12, 1167-1181. Research Article ISSN 2278 4357

FORMULATION DEVELOPMENT AND EVALUATION OF

KETOROLAC IMMEDIATE RELEASE SUMATRIPTAN SUSTAINED
RELEASE BILAYER TABLETS

S. Ramulu*, V. Jayanth.

Department of Pharmaceutics, Malla Reddy Pharmacy College, Maisammaguda,

Secunderabad.

ABSTRACT
Article Received on
03 Oct 2014, The present study is concerned with formulation development and
Revised on 27 Oct 2014, evaluation of ketorolac immediate release and sumatriptan sustained
Accepted on 20 Nov 2014
release bi-layered tablet. An attempt was made to develop bi-layer
tablet suitable for delivering different drugs with different release
*Correspondence for Author pattern like one layer of drug as immediate release to get quick relief
S. Ramulu
and second drug as sustained release of drug which gives effect of drug
Department of Pharmaceutics,
for sufficient long time and reduce frequency of dose. In the bi-layered
Malla Reddy pharmacy
college, Maisammaguda, tablet the immediate layer were prepared by direct compression
Secunderabad, India. method by using super disintegrants such as cross carmellose sodium
,sodium starch glycolate and sustained layer were prepared by wet
granulation method using polymers such as hydroxy propyl methyl cellulose, ethyl cellulose
and pvp k-30.The prepared formulations were evaluated for their physicochemical
characteristics, bulk density, tapped density, angle of repose, compressibility index,
hauseners ratio, and In vitro drug release studies . The formulation having immediate release
layer produces immediate effect 98% in 60 minutes followed by sustained release effect
97.5% up to 8 hours. With the data of kinetic analysis, F9 formulation showed best linearity
in Higuchis Equation plot indicating that the release of drug from matrix tablet follows Non
Fickian diffusion.

KEYWORDS: Bi-layered tablet, ketorolac, sumatriptan, Immediate Release, Sustained

Release, Higuchi euation.

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INTRODUCTION [1,2]
Drug delivery systems (DDS) are a strategic tool for expanding markets/indications,
extending product life cycles and generating opportunities. Oral administration is the most
popular route for systemic effects due to its ease of ingestion, pain avoidance, versatility and
most importantly patient complia A solid dosage form is drug delivery system that includes
tablets, capsules, sachets and pills as well as a bulk or unit-dose powders and granules.
Among the various dosage forms oral solid dosage forms have greater importance and
occupies a prime role in the pharmaceutical market. Oral route of drug administration is
widely acceptable and drugs administered orally as solid dosage form represents the preferred
class of products. Over 90% of drugs formulated to produce systemic effects are produced as
solid dosage forms. Because of these reason whenever New chemical entity (NCE) has
discovered, which shows a sufficient pharmacological action, first the pharmaceutical
company asks whether the drug is successfully administered by oral route or not. The oral
route of administration still continues to be the most preferred route due to its manifold
advantages including

The goal of sustained release dosage form is to maintain therapeutic blood or tissue levels of
the drug for an extended period. This is usually accomplished by attempting to obtain zero
order release from the dosage form. Zero order release constituents drug release from the
dosage form that is independent of the amount of drug in the delivery system (a constant
release rate). Sustained release system generally do not attain this type of release and usually
try to mimic Zero order release by providing drug in a slow first order fashion
(concentration dependent).Systems that are designated as prolonged release can also be
considered as attempts at achieving sustained release delivery.

Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two
incompatible substances and also for sustained release tablet in which one layer is immediate
release as initial dose and second layer is maintenance dose. In which the one layer is
formulated to obtain immediate release of the drug, with the aim of reaching a high serum
concentration in a short period of time. The second layer is a controlled release, which is
designed to maintain an effective plasma level for a prolonged period of time. The
pharmacokinetic advantage relies on the fact that drug release from fast releasing layer leads
to a sudden rise in the blood concentration. However, the blood level is maintained at steady
state as the drug is released from the sustaining layer.

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Ketorolac [3]
Ketorolac tromethamine is a non steroidal anti inflammatory drug (NSAID)that exhibits
analgesic activity mediated by peripheral effects. Ketorolac inhibits the synthesis of
prostaglandins through inhibition of the cyclo-oxygenase enzyme system. At analgesic doses,
it has minimal anti-inflammatory & anti pyretic activity.

Sumatriptan [4]
Sumatriptan Succinate is a selective 5-hydroxytryptamine1 (5-HT1) receptor subtype agonist.
category belongs to Anti-migraine agent. Sumatriptan is an agonist for a vascular 5-
hydroxytryptamine1 receptor subtype (probably a member of the 5-HT1D family) having only
a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity (as
measured using standard radio ligand binding assays) or pharmacological activity at 5-HT2,
5-HT3, or 5-HT4 receptor subtypes or at alpha1 -, alpha2-, or beta-adrenergic; dopamine1;
dopamine2 ; muscarinic; or benzodiazepine receptors. The vascular 5-HT1 receptor subtype
that sumatriptan activates is present on cranial arteries in both dog and primate, on the human
basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction.
This action in humans correlates with the relief of migraine headache.

MATERIALS AND METHODS

MATERIALS
Sumatriptan and ketorolac was obtained as a gift samples from Chandra laboratories,
Hyderabad. , Ethyl cellulose and Hydroxy propyl methyl cellulose,pvpk-30 was purchased
from Myl Chem Mumbai. Starch, cross povidone, CCS, SSG, Talc, Magnesium stearate,
Starch, MCC was purchased from S.D.FineChem.Ltd., Mumbai. All other chemicals and
solvents were purchased from analytical grade

METHODS
Blend Preparation of Immediate Release Layer of Ketorolac
The dose of ketorolac for immediate release was fixed as 150mg.immediate release layer of
ketorolac(F1-F6) were prepared by direct compression technique as per the composition
Table1. All the ingredients were passed through sieve and mixed in a motor and pestle for
30min for uniform mixing. The addition of ingredients was done in a geometrical manner.
Then the Ketorolac layer was compressed using 8mm round punch.

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Composition of Immediate Release Layer

Table no:1- composition of immediate release layer of ketorolac
FormufFormulation F1 F2 F3 F4 F5 F6
Ketorolac 10mg 10mg 10mg 10mg 10mg 10mg
CP 7.5mg 11.25mg - - - -
CCS - - 7.5mg 11.25mg - -
SSG - - 7.5mg 11.25 mg
MCC 128mg 124.25mg 128mg 124.25mg 128mg 124.25mg
Magnesium stearate 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg
Talc 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg
Total weight 150 150 150 150 150 150
CP- cross povidone, CCS: Cross caramellose sodium, SSG: Sodium starch glycolate, MCC-
Micro crystalline cellulose.

Granule Preparation of Sustained Release Layer of Sumatriptan

The dose of sumatriptan for sustained release was fixed as 300mg. The sustained layer of
sumatriptan(F1-F9) was prepared by wet granulation technique with various excipients as for
the formula given in table 2, The active ingredient was passed through the sieve#40 followed
by the other ingredients were passed the same sieve. Sumatriptan, HPMC,EC, MCC were
taken in a poly bag and mixed for 5minutes to ensure uniform mixing of the ingredients with
the drug. Weigh PVP K-30 accurately and it is mixed with water to form a paste is used as
binder solution and kept separately. The binder solution was added slowly to the dry mixed
ingredients with constant mixing till to get solid mass to form uniform and optimum granules.

Then the wet granules were dried in trays and pass the air for drying . The dried materials
were passed through the sieve#20. After sieving dry granules were lubricated using
Mg.stearate and Talc.

Composition of Sustained Release Layer

Table no:2- formulation table for sustained release layer

Ingredients(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9
Sumatriptan 100 100 100 100 100 100 100 100 100
HPMC 30 45 60 75 -- -- -- -- 30
EC -- -- -- -- 30 45 60 75 15
Talc 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
PVP K-30 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
Magnesium stearate 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
MCC q.s q.s q.s q.s q.s q.s q.s q.s q.s
Aspartame 3 3 3 3 3 3 3 3 3
Water q.s q.s q.s q.s q.s q.s q.s q.s q.s
Total weight 300 300 300 300 300 300 300 300 300

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Evaluation Parameters
1. Bulk Density
It is the ratio of total mass of powder to the bulk volume of powder. It was measured by
pouring the weighed powder into a measuring cylinder and the volume was noted. It is
expressed in gm/ml. (Table no: 3,4)
Bulk density = Weight of powder / Bulk volume.

2. Tapped Density
It is the ratio of total mass of powder to the tapped volume of powder. It is determined by
placing a graduated cylinder containing known weight of powder, mechanical tapper
apparatus operated for fixed number of taps until the powder bed volume has reached a
minimum volume. (Table no: 3,4)
Tapped density = Weight of powder / Tapped volume.

3. Carrs Index (i)

It is measured by using values of bulk density and tapped density.(Table no: 3,4)
Tapped density - Bulk density
100
Tapped density

4. Hausners Ratio
Hausners ratio is the ratio of tapped density to bulk density.(Table no: 3,4)
Tapped Density
Hausners Ratio =
Bulk Density

5. Angle of Repose
The frictional forces in a loose powder can be measured by the angle of repose, .(Table no:
3,4)

= tan-1 (h/r)
Where h=height of the heap
r=radius of the heap
It is determined by pouring the powder a conical on a level, flat surface, measured the
included angle with the horizontal.

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6. Hardness
The hardness of the tablet was determined by using a Monsanto hardness tester. It is
2
expressed in Kg / cm .

7. Thickness
The thickness of the tablets was measured by Digital Vernier Caliper. It is expressed in mm.

8. Weight Variation
Ten tablets were selected randomly from the lot and weighed individually to check for weight
variation. The following %deviation in weight variation is allowed.

9. Friability (F)
The friability of the tablet was determined using Roche Friabilator. It is expressed in %. 10
tablets were initially weighed and transferred into the friabilator. The friabilator was operated
at 25 rpm for 4 mins. The tablets were weighed again. Friability of tablet should not exceed
1%.

10) Drug Content

For determination of drug content three tablets from each formulation were weighed
individually and powdered. The quantity of powder was equivalent to 10 mg. The equivalent
weight ketorolac and sumatriptan were transferred into 100 ml volumetric flask diluted to
100ml with sufficient amount of phosphate buffer (pH6.8). Then aliquot of the filtrate was
diluted suitably and analyzed spectrophotometrically at 322 and 282nm against blank.

11) a) In Vitro Dissolution Studies for Sustained Release Layer of Sumatriptan

In vitro drug release studies were carried out using USP XXIV dissolution apparatus type II,
with 900ml of dissolution medium maintained at 371C for 8 hr, at 50 rpm, 0.1 N HCl was
used as a dissolution medium for first 2 hours and 6.8 pH phosphate buffer for next hours.
5ml of sample was withdrawn at predetermined time intervals replacing with an equal
quantity of drug free dissolution fluid. The samples withdrawn were filtered through 0.45
membrane filter, and drug release in each sample was analyzed after suitable dilution by
UV/Vis Spectrophotometer at 282nm.(Table.no.-6)

b) In Vitro Dissolution Studies for Immediate Release Layer of Ketorolac

In vitro drug release studies were carried out using USP XXIV dissolution apparatus type II,
with 900ml of dissolution medium maintained at 371C for 1 hr, at 75 rpm, 0.1 N HCl was

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used as a dissolution medium. 5ml of sample was withdrawn at predetermined time intervals
replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn were
filtered through 0.45 membrane filter, and drug release in each sample was analyzed after
suitable dilution by UV/Vis Spectrophotometer at 322nm.(Table.no-6.1)

12. Ft-ir Studies

These studies are used to analyze the functional groups of drug and excipients. (Figure )

FTIR spectra of Sumatriptan pure

FTIR spectra of Ketorolac

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FTIR Spectra of Bilayer tablet

FTIR-spectra data of bilayer tablet

Functional Characteristic Observed peak for drug cm-1 Peaks for optimized
Sno
group peak cm-1 SUMATRIPTAN KETOROLAC formulation
1 N-H Stretch 3500-3300 3380 3480
2 CH3 2960-2850 2931 2918
3 SO2 1420-1330 1380 1385
4 C=O 1150-1040 1145 1113

Drug Release Kinetics

To analyze the mechanism of drug release from the tablets, the results of in vitro release data
were plotted in various kinetic models like zero order, Higuchi model and Korsmeyer-
peppas.

RESULTS AND DISCUSSION

Evaluation Parameters
Tablets of different formulations were subjected to various physicochemical evaluation
parameters such as weight variation, hardness, friability, thickness, drug content, and
diameter. The results of these studies were found to be within the limits and given in Table
no.3.

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Compatibility Study
The standard spectrum of ketorolac and sumatriptan was compared by FTIR spectrum of
physical mixtures fig. and .FTIR studies proved that the drug is compatible with excipients.

In-Vitro Dissolution Studies

In vitro Dissolution Studies for Immediate Release Layer of Ketorolac
In vitro drug release studies were carried out using USP XXIV dissolution apparatus type II,
with 900ml of dissolution medium maintained at 371C for 1 hr, at 75 rpm, 0.1 N HCl was
used as a dissolution medium. The dissolution rate was found to with increasing
concentration of sustained release agent. formulation F1,F2,and F3 which contain
CP,CCS,SSG shows % drug release of 25%,60.4% and 62% Formulations F4,F5 and F6
shows % percentage drug release of 80%,67% and 98% respectively. The percentage drug
release of all the formulation shows in (table. no 6.1).

In Vitro Dissolution Studies for Sustained Release Layer of Sumatriptan

In vitro drug release studies were carried out using USP XXIV dissolution apparatus type II,
with 900ml of dissolution medium maintained at 371C for 8 hr, at 50 rpm, 0.1 N HCl was
used as a dissolution medium for first 2 hours and 6.8 pH phosphate buffer for next hours.
The dissolution rate was found to with increasing concentration of sustained release agent.
formulation F1,F2,F3 and F4 which contain HPMC shows % drug release of
99.8%,96.3%,98.1 and 98.4% Formulations F5,F6,F7,F8 and F9 shows % percentage drug
release of 79%,75.4% , 74.9%,74.1% and 97.5% respectively. The percentage drug release of
all the formulation shows in (table.6).

Release Kinetics
Different models like zero order, first order, higuchi's, and peppas plots were drawn for
formulation F-9. The regression coefficient (r2) value for zero order, first order, higuchi's, and
peppas plots (figures no:3,4,5,6 and table no: 7) for formulation F-9 was found to be 0.981,
0.816, 0.955, and 0.552 respectively.

Table.no:3 Flowproperties of sumatriptan

Angle of Loose Tapped Hausners
Formulations Repose () Bulk Bulk %Compressibility ratio
F1 27.5 0.33 0.38 13.16 1.15
F2 25.3 0.37 0.43 13.95 1.16
F3 28.1 0.34 0.39 12.82 1.15

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F4 26.8 0.38 0.44 13.64 1.16

F5 27.4 0.34 0.39 12.82 1.15
F6 25.9 0.32 0.37 13.51 1.16
F7 26.4 0.36 0.41 12.2 1.14
F8 25.9 0.34 0.39 12.82 1.15
F9 29.1 0.3 0.35 14.29 1.17
From the above pre-compression parameters it was clear evidence that granules have
excellent flow properties.

Tablet no:4-Post Compression Parameters for Sustained Release Tablet

Hardness Thickness Friability Weight Drug
F.CODE
(kg/cm2) (mm) (%) variation content(%)
F1 8.5 4.65 0.24 300 99.2
F2 8.3 4.47 0.25 299 99.1
F3 8.0 4.87 0.35 297 98.9
F4 7.4 5.33 0.56 302 97.6
F5 7.6 5.84 0.45 300 99.2
F6 7.9 5.51 0.25 298 99.9
F7 8.2 5.64 0.21 300 100.1
F8 8.4 5.92 0.30 301 99.7
F9 7.4 5.33 0.41 300 99.1

Table.no:5 Flowproperties of ketorolac

Formulations Angle of Loose Bulk Tapped Bulk %Compressibility Hausners
Repose () Density (g/ml) Density (g/ml) ratio
F1 26.3 0.41 0.47 12.77 1.15
F2 27.4 0.32 0.37 13.51 1.16
F3 25.8 0.34 0.39 12.82 1.15
F4 25.3 0.44 0.54 18.52 1.23
F5 28.9 0.42 0.48 12.5 1.14
F6 24.7 0.45 0.51 11.76 1.13

Table.no-6-In Vitro Drug Release Studies for SR tablets

Time(hrs_) F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
0.5 20.8 16.2 19.1 18.5 19.3 15.4 15.1 14.9 11.9
1 33.1 27.1 24.9 25.7 24.6 22.1 23.8 22.5 22.6
2 49.2 38.3 36.5 34.9 39.5 34.4 32.4 35.9 37.1
3 69.4 56.1 51.9 49.5 47.3 45.8 43.8 41.6 43.5
4 78.1 64.8 64.7 63.2 58.2 51.5 49.6 52.5 51.8
5 99.8 83.1 87.2 85.4 64.7 57.2 59.4 59.1 69.4
6 96.3 98.1 98.4 71.5 66.9 64.1 65.4 83.9
8 79 75.4 74.9 74.1 97.5

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Figure.no:1 - dissolution graph for sustained release formulations

Table .no: 6.1- Dissolution for immediate release tablet of Ketorolac

Time F1 F2 F3 F4 F5 F6
5 3.76 3.53 9 12 12 10
10 11.7 8.24 18 28 24 21
15 8.01 13.6 33 36 38 42
30 15.5 33.92 41 52 43 54
45 20.2 49.71 53 69 58 68
60 25 60.4 62 80 67 98

Figure no:2- Dissolution graph for formulations F1-F6

Kinetic Release Models

Table no.7- release kinetics for F9 formulation for sustained release layer

ZERO FIRST HIGUCHI PEPPAS

%CDR Vs T Log % Remain Vs T %CDR Vs T Log C Vs Log T
Slope 12.064 -0.1904906 35.543568 1.1155874
Intercept 6.9774 2.1728418 -10.2185669 1.02790566
Correlation 0.9907 0.9034658 0.97727288 0.74327680
R2 0.9815 0.8162505 0.95506229 0.5524604

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Fig no:3 - zero order release graph for F9 sustained release formulation

Fig no:4 - First order release graph for F9 sustained release formulation

Fig no:5 - Higuchi model graph for F9 sustained release formulation

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Fig no:6- peppas model for F9 sustained release formulation

Table.no:8- Pre-formulation parameters for immediate release tablets

Physical parameters F1 F2 F3 F4 F5 F6
Weight variation 147 148 148 149 149 151
Hardness
5.5 4.5 5.3 4.5 4 4.3
(Kg/cm2)
Thickness
2.68 2.64 2.65 2.27 2.52 2.52
(mm)
Friability % 0.37 0.41 0.42 0.38 0.39 0.41
7min 5min 2min
Disintegration time 8min 5min 3min
20sec 40sec 30sec
Drug content% 99.4 99.3 100.2 100.1 99.6 99.2

Evaluation parameters for bilayered tablet K.S(Ketorolac and sumatriptan)

F.CODE Hardness (kg/cm2) Thickness (mm) Friability (%) Weight variation

5.710.7 0.28 4520.71
KS 8.1 24

Table.no:9- Dissolution profile of bi-layered tablet

Percentage drug released (%)

S.NO Sampling time
KETOROLAC SUMATRIPTAN
1 0.15 15 5.2
2 1hr 98 21.9
3 2hr -- 34.6
4 3hr -- 42.7
5 4hr -- 57.6
6 5hr -- 69.3
7 6hr -- 84.9
8 8hr -- 97.5

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Fig no:7

SUMMARY AND CONCLUSION

Both immediate release and sustained release formulation are prepared and contain in a single
dosage form. The study describes the formulation of both immediate and sustained release
drug for increased therapeutic efficacy and patient convenience. The bi-layer tablets were
prepared by Direct compression technique for immediate layer and Wet granulation for SR
and tried for the good release behavior by taking various polymers. Suitable formulation has
been optimized.. During pre-formulation it has been observed that there is no drug-drug and
drug excipients interaction, so the excipients which have been selected for the formulation are
compatible with the drugs.

This system provides zero order or near zero order release for IR layer and SR layer provides
Higuchi model via non-fickian diffusion controlled release mechanism after the intial burst
release. This concept also demonstrates a wide technology for various applications such as
instant release/slow release from one dosage form, because It allows the precise modulation
of drug release process even for drug characteristics by extreme physicochemical properties.

The bi-layer tablets of ketorolac and sumatriptan containing immediate release layer and
sustained release layers were prepared by using different polymers. Among all the
formulations the best formulation(KS) shown a prolonged sustained action up to 8 hours with
the drug result of 97.43%. By this technology we reduced the dosing frequency thereby
increase the patient compliance when compared to conventional dosage form.

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ACKNOWLEDGMENT
Would like to thanks Mr. mohammad imran, Chandra labs, providing all equipments and
instruments.

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