Latin American Journal of Pharmacy Regular Article

(formerly Acta Farmacéutica Bonaerense) Received: September 14, 2011

Revised version: November 20, 2011
Lat. Am. J. Pharm. 30 (10): - (2011) Accepted: November 21, 2011

Development and Evaluation of Naproxen

Sodium 250 Mg Effervescent Tablets

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M. Harris SHOAIB 1*, Muhammad GHIASUDDIN 1, Rabia I. YOUSUF 1,

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Wajhia EFFET 2, Iyad N. MUHAMMAD 1 & Muhammad HANIF 1

1 Department of Pharmaceutics, Faculty of Pharmacy, University of Karachi, Karachi-75270, Pakistan.

2 Dow College of Pharmacy, Dow University of Health Sciences, Karachi, Pakistan

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SUMMARY. Effervescent tablets have always been convenient, simple and measured dosage form. The
phenomenon of carbonation, in this type of dosage form, accelerates the solubility and enhances the
bioavailability of the drug and the addition of flavorant also masks the objectionable taste of the medica-
ment in a more patient compliant way. The present study focuses on developing a new, simple, cost effec-
tive formulation of naproxen sodium 250 mg as an effervescent tablet using direct compression technique.
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Nine different trial formulations of naproxen 250 mg were designed with varying proportions of sodium
carbonate, sodium bicarbonate, citric acid and PEG 6000 and were prepared by direct compression
method, and evaluated for pharmaceutical quality attributes. Quality assessment proved formulations F8
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as a satisfactory one showing respectively mean weight of 2200 ± 50.52 having hardness and friability of
14.78421 ± 1.3791 kg and 1.241 %. Tablets took 4 min and 36 s to disintegrate completely. The average pH
of the solution was within the range of 5.65 to 5.85. Dissolution profile comparison with the conventional
formulation was carried out and maximum drug release by the trial formulation was observed within 15
min. spectrophotometric determination of drug content was found to be 99.82 ± 1.754. Stability characteri-
zation was also conducted on the formulations under stress (40 °C/75 % R.H.) that showed formulations
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remained stable throughout the study duration with acceptable difference in physical and chemical char-
acteristics. Such formulations increases patient compliance and have possibly improved bioavailability.
The work also emphasizes on the benefit of using direct compression method as a cost effective technique
in terms of process, materials handling with productivity.
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INTRODUCTION pains 8. It has also shown promising pain killing

Effervescent mixtures have been known for effect in migraine attacks 9.
250 years 1 for being convenient, easy to use, Among the oral pharmaceutical dosage
premeasured dosage form 2. Many studies have forms, tablets are the most popular one, ac-
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been conducted in past comprising on use of ef- counting for about 70 % of all pharmaceutical
fervescent mechanism in order to improve the preparations available 10 and according to a sur-
drug delivery, enhance the bioavailability and vey, direct compression is the preferred manu-
make the product patient friendly 3. facturing process for pharmaceutical tablets 11
Mostly bioavailability issues are not challeng- that has increased steadily over the years be-
ing for drugs belonging to NSAIDs class 4-7. cause of its many advantages over other manu-
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Naproxen belongs to the same class relieving facturing processes 12. Pharmaceutical market
pain by COX inhibition and effectively used in shows an increasing interest in fast disintegrat-
the management of headaches, muscle aches, ing tablets due to their good acceptability
backaches and pains associated with tendinitis, among certain age groups and other patients
bursitis, arthritis, menstrual cramps and dental with difficulties in swallowing conventional oral

KEY WORDS: Direct compression effervescent tablet, Naproxen, Pharmaceutical evaluation, Tableting technique.
* Author to whom correspondence should be addressed. E-mails: [email protected], [email protected]

ISSN 0326-2383 1
SHOAIB M.H., GHIASUDDIN M., YOUSUF R.I., EFFET W., MUHAMMAD I.N. & HANIF M.

solid dosage forms 13. Effervescent technique Rotary Compression Machine D3B (Eng-
can accelerate drug disintegration and dissolu- land) equipped with round flat 20 mm diameter
tion, is usually being applied for quick release set of punches and dies. Electronic balance
preparations therefore it has gained tremendous (Mettler Toledo B204-S), beaker (Pyrex, Eng-
interest by the consumers 14. In the present land), hardness tester (Fujiwara, Seisukusho
study the effervescence was achieved by neu- Corporation, Japan) friabilator (H.Jurgens and
tralization reaction that required three molecules Co- GmbH and Co-D2800, Bremen, Germany).

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each of sodium carbonate and sodium bicarbon- Disintegration test apparatus (Erweka, DT, Ger-
ate to neutralize two and one molecule of citric many), fissolution apparatus (Erweka DT,

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acid as shown by Eqs. [1-2] 15: Heusenstamm, Germany), tablet harness tester
(Ogawa Seiki Co. Ltd, Tokyo, Japan).
3 Na2CO3 + 2 C6H8O7 = 3 CO2 + 3 H2O
+ 2 Na3C6H5O7 [1] Preparation of Naproxen tablets
3 NaHCO3 + C6H8O7 = 3 CO2 + 3 H2O Designing the tablet composition
+ Na3C6H5O7 [2] The quantities of citric acid, sodium carbon-

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ate and sodium bicarbonate were derived ac-
Inappropriately selected quantities of alkali cording to the Eqs. [1] and [2].
and acid will not produce effervescence special- Manufacturing process
ly when citric acid remains un-reacted due to Tablets preparation was carried on under
developed acidity that also delays disintegration low moisture environment to prevent early ef-
time and remains less effective in masking ob- fervescence reaction of the formulation ingredi-
jectionable taste of drug 16, therefore in this ents. All the ingredients were accurately
study nine trial formulations of naproxen 250
mg were prepared with varying proportions of
sodium bicarbonate, sodium carbonate, citric
D weighed using electronic balance (Mettler Tole-
do B204-S) as mentioned in Table 1. Weighed
powders for 100 tablets were passed through 20
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acid and polyethylene glycol PEG 6000 (Table mesh sieve then were blended for about 5-7
1) to obtain best optimized formulation. min in a locally made 500 g capacity drum mix-
er (Sayyed Engineering, Karachi) and compres-
MATERIAL AND METHOD sion was carried out by a single punch com-
Equipment and Chemicals pression machine (Erweka, Korsch, Germany)
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Naproxen sodium was kindly gifted by Plat- equipped with round flat 20 mm diameter set of
inum Pharmaceuticals Pvt. Ltd, sodium bicar- punches and die. The tablet formulations were
bonate, sodium carbonate, PEG 6000, citric acid individually wrapped in an aluminum foil
anhydrous, dye yellow orange F.D & C.No.6, pouch.
mannitol, citric acid anhydrous, aspartame, sodi-
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um cyclamate, lemon flavor (all chemicals used Evaluation of tablet properties

were procured from Merck, Darmstadt, Ger- After compression, a number of different
many). pharmacopeial and non-pharmacopeial physico-

Amount of ingredients mg / Tab

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Formulation ingredients
F1 F2 F3 F4 F5 F6 F7 F8 F9

Naproxen Sodium 250 250 250 250 250 250 250 250 250
Sodium Bicarbonate 600 570 630 700 730 765 800 830 900
Sodium Carbonate 100 100 100 100 100 100 100 100 100
Citric Acid Anhydrous 500 550 600 650 675 700 725 750 800
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PEG 6000 75 75 75 75 75 25 25 25 25
Dye Yellow Orange F.D.C. No.6 3 3 3 3 3 3 3 3 3
Mannitol 100 100 100 100 100 100 100 100 100
Aspartame 15 15 15 15 15 15 15 15 15
Sodium Cyclamate 10 10 10 10 10 10 10 10 10
Lemon Flavor 47 47 47 47 47 47 47 47 47
Total tab. weight mg 1700 1720 1830 1950 2005 2015 2075 2130 2250
Table 1. Composition of different formulations of naproxen effervescent tablets having fixedconcentration of
mannitol, aspartame, sodium cyclamate and lemon flavor.

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 Latin American Journal of Pharmacy - 30 (10) - 2011

chemical tests were performed on all three for- tion in water having 0.262 % of monobasic sodi-
mulations, discussed as under: um phosphate and 1.15 % anhydrous dibasic
Weight variation and Hardness Evaluation sodium phosphate. The withdrawn sample was
The variation of the weight of individual refreshed each time with same quantity of medi-
tablet is a valid indication of the corresponding um. The dissolution profile of the trial batches
variation in the drug content 17. Twenty tablets were compared with that of conventional re-
were taken at random and were evaluated for lease naproxen sodium brand by a multinational

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weight variation and hardness. Not more than manufacturer kept as reference standard 22.
two of the individual weights were allowed to Solution pH Test

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deviate from the average weight by more than For the pharmaceutical preparations that are
the percentage deviation shown and none by intended to be taken orally, the pH of the solu-
more than that percentage. 18. Hardness was tion is a vital characteristic as the nature of the
kept above 5 kg and out of twenty tablets, only excipients used in effervescent tablets causes
two were allowed to exceed the limit. The mean the establishment of a buffer solution but as the
hardness ± S.D. of each formulation is mention time passes, the effervescent tablets shows

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in Table 2. acidic pH due to the degradation of carbonic
Friability Test acid. the change in the pH 22. A test unique to
Tablets friability test was conducted accord- effervescent tablets was the solution pH gener-
ing to the British Pharmacopeia. The loss in ated when the tablet was dissolved and pH was
tablet weight after the test indicates the ability of measured immediately at the completion of ef-
the tablets to withstand shocks and abrasions 18. fervescent reaction and was performed for ten
Disintegration Test tablets. The constant solution pH is a sign of
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The disintegration time limit was set as per
the British Pharmacopeia 19. The Disintegration
was evaluated to ensure the availability of drug
good distribution of raw material in the tablet. A
wide variation of pH from tablet to tablet indi-
cates non-homogenous granulation directly pri-
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at the site of absorption 20. The test was per- or to tableting.
formed on six tablets from each batch; tablet
was placed in a beaker containing 200 mL water Taste masking property of the preparation
at a temperature of 15-25 °C and observed for The solution prepared as a result of efferves-
reaction and the time taken by tablet to disinte- cence was tasted to check the taste masking
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grate was recorded by stop watch. tendency of the formulation. As a matter of ef-
Dissolution Test fervescent tablet manufacturing the most com-
Dissolution test of the trial formulations was patible and compliant flavors used in this type
carried out according to USP30 dissolution test- of dosage form used to be citrus or berry flavors
ing for conventional tablets 21, as similar dissolu- for being stable in slight acidic pH range 22. In
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tion studies are conducted for effervescent. The the present study citrus lemon was added as a
dissolution medium consisted of 900 mL of 0.1 flavorant that had a slight acidic pH formation in
M pH 7.4 phosphate buffer which was w/v solu- the solution with orange dye (Table 1).
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Disintegration Solution pH Assay Hardness

Pharmaceutical
(min, n = 6) Test (n = 10) (%, n = 20) (kg, n = 20)

Limits < 3 min 5.65-5.85 98.5-100.5 % 15 ± 2

Formulations

F 1 5.45 ± 0.58 5.20 97.09 ± 1.217 10.11 ± 0.99

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F 2 6.11 ± 0.60 5.30 97.01 ± 2.143 17.01 ± 0.72

F 3 4.35 ± 0.48 5.45 98.84 ± 1.893 14.78 ± 1.37
F 4 5.40 ± 0.51 5. 75 97.23 ± 1.675 17.58 ± 0.93
F 5 5.19 ± 0.46 5. 83 98.13 ± 2.723 18.00 ± 0.95
F 6 5.02 ± 0.29 5.84 98.56 ± 1.974 17.34 ± 0.99
F 7 4.43 ± 0.27 5.65 97.88 ± 2.156 17.09 ± 0.71
F 8 3.03 ± 0.24 5.75 99.82 ± 1.754 14.82 ± 0.98
F 9 4.36 ± 0.30 5.83 97.67 ± 1.587 14.81 ± 1.34
Table 2. Physical characteristics of the effervescent tablets developed.

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SHOAIB M.H., GHIASUDDIN M., YOUSUF R.I., EFFET W., MUHAMMAD I.N. & HANIF M.

Assay of active ingredients

The quantitative assay of naproxen sodium
effervescent tablet trial formulations were car-
ried out spectrophotometrically according to
USP specifications. Twenty tablets were
weighed and powdered and aliquot equivalent

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to weight of one tablet was utilized in order to
prepare the working strength of 0.005 % in

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methanol. Absorbance of the sample was taken
at 331 nm and compared with that of reference
standard prepared in same strength using same
solvent 15. Figure 1 Dissolution studies of Naproxen Sodium Ef-
fervescent Formulations. (n = 6).
Stability Studies

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The best effervescent tablet fromualtion F8 tions tested, formulations 3, 6 and 8 have shown
that qualified for its attributes was subjected to results as per the specifications.
stability evaluation under accelerated conditions All of the formulations have shown the
at 40 °C and 75 % R.H. in stability testing cham- weight variation under the specified pharma-
ber (NuAire, Plymouth, MN 55447 USA) accord- copeial limits i.e., ± 5 %. The mean weights of
ing to the ICH guidelines 23. The samples were tablets in the aforementioned formulations were
kept in amber glass bottle with plastic closure. 1712.90 ± 30. 8, 1726.40 ± 15.7, 1830.65 ± 32.0,
The study period was six months and frequency D 1934.55 ± 63.9, 2005.00 ± 58.1, 2015.15 ± 17.0,
of sampling was kept at 0, 1, 3 and 6 months 2075.40 ± 36.3, 2130.25 ± 42.6, 2249.90 ± 16.9 in
(Table 3). mg for F1–F9, respectively. The fulfillment of
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pharmacopeial limits indicates not only satisfac-
RESULTS AND DISCUSSION tory flow properties but also the proper blend-
The current work represents the preparation ing of ingredients for the proposed formulation.
and pharmaceutical evaluation of effervescent The hardness of the effervescent tablet was as
tablets containing Naproxen 250 mg by direct less as 10.11 ± 0.99 kg.N. for F1 formulation to
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compression method. Nine different formula- as harder tablet as 18 ± 0.95 kg.N. for F5 formu-
tions of Naproxen sodium 250mg were tested lation. Although it is well known that lubricants
having different proportions of sodium carbon- can affect tablet hardness when used in too
ate, sodium bicarbonate, citric acid and PEG high concentration or mixed for too long a peri-
6000 (Table 1). od, improper mixing of glidant have been re-
ported to cause weight variation by not allowing
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Based on physical test characterization, dis-

solution studies (Fig. 1), among all the formula- the uniform flow of the powder 24. The tablets

Formulation 3 (n=6) Formulation 6 (n=6) Formulation 8 (n=6)

Pharmaceutical
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Evaluation Month(s) Month(s) Month(s)

1st 3rd 6th 1st 3rd 6th 1st 3rd 6th

Friability (%) 3.201 3.001 3.101 2.501 2.301 2.301 1.243 1.245 1.243

Disintegration (min.s) 2.45 2.45 2.45 2.14 2.34 2.24 2.34 2.33 2.35
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Solution pH test 5.861 5.881 5.851 5.705 5.711 5.712 5.775 5.775 5.775

Assay % 98.04 97.75 97.19 98.56 98.17 97.78 99.82 99.03 98.80
2034.00 2033.05 2032.05 2376.15 2376.15 2376.15 2221.50 2221.90 2221.70
Weight (mg)
± 770 ± 770 ± 770 ± 102 ± 102 ± 102 ± 500 ± 500 ± 500

10.11 10.11 10.15 17.09 17.11 17.01 14.82 14.82 14.82

Hardness (kg)
± 1.19 ± 1.19 ± 1.19 ± 0.71 ± 0.71 ± 0.71 ± 1.37 ± 1.37 ± 1.37

Table 3. Stability studies of the optimized effervescent tablet formulations.

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 Latin American Journal of Pharmacy - 30 (10) - 2011

formulation systems with such ingredients may

affect the dissolution and absorption of the drug
22, therefore buffered medium is always recom-

mended as dissolution media for effervescent

tablets, the release of 99 % of the drug was

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achieved within 15 min, this was in conforma-
tion with the requirement for effervescent tablet
formulation (Fig. 1).

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The assay result was ranging from as low as
97.01 for F2 till as maximum as 99.82 % for F8,
others mentioned in Table 2. The results were
Figure 2. Similarity between Ref Conventional Tab. in line with the set limit specified in B.P. On
and Effervescent Tab. (n=6). pharmaceutical stability assessment, F8 has
shown most stable tablets under stress (40 °C/75

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hardness of formulations F3, F6 and F8 were % R.H.) conditions (Table 3). It was observed
14.78 ± 1.37, 17.34 ± 0.99 and 14.98 ± 0.87, re- that as an increase in sodium bicarbonate and
spectively, in kg.N. The lubricant coats the gran- anhydrous citric acid had a significant effect on
ulation particles and interferes with tablet bond- the physicochemical behavior of the dosage
ing 25. Friability of the formulations was ob- form. The ratio of both the components was
served to be according to the pharmacopeial set added as to neutralize the effervescence reac-
limits i.e., < 1.5 % for the formulations. The fri-
D tion the same was observed in Solution pH test
ability data was 3.09 ± 0.6, 2.53 ± 0.77, 1.73 ± but furthermore it also has been observed to im-
0.42, 3.2 ± 0.58, 2.12 ± 0.6, 1.74 ± 0.47, 2.5 ± prove the hardness and friability of the formula-
0.67, 1.19 ± 0.41 and 1.39 ± 0.64 in % for the tions F5–F9. Accelerated stability studies of three
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formulations F1-F9, respectively. selected formulations also promoted F8 formula-
Results revealed that hardness, friability, dis- tion due to best assay results, constant hardness,
integrating time and dissolution profile of F8 is less weight variation, constant friability and con-
best as compare to all other formulations as stant disintegration time as shown Table 3.
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shown in Figure 1. Since dissolution of a drug

from the fragmented F8 tablet appears to partial- CONCLUSION
ly or completely control the appearance of the As a conclusion, effervescent naproxen 250
drug in the blood; disintegration is used as a mg tablets were effectively prepared by direct
guide to the formulator in the preparation of the compression method. It was further observed
optimum tablet formula i.e., F8 and in process that formulation F-8 was the most optimum for-
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control test to ensure lot to lot uniformity 26. mulation for naproxen 250 mg effervescent
Nevertheless, one should not expect a correla- tablet. This type of formulation increases patient
tion between disintegration and dissolution 27, compliance, acceptance and have improved
as he former represents the breakdown of the bioavailability showing better effects pharmaco-
dosage form into particles while the later con- dynamically. Such studies would guide the re-
searchers and manufacturers in improvising the
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version of particulates into solution. The aver-

age pH of the Solution for formulations were re- pharmacologic effects of the drug by enhancing
quired to be in a range of 5.65 to 5.85, all the its pharmacokinetics, moreover, make drug for-
formulations have shown pH under the same mulation simple and cost effective.
range.
In the comparison of dissolution profile, the Aknowledgment. Authors are especially thankful to
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department of Pharmaceutics, faculty of pharmacy,

prepared effervescent tablet, F8 has shown a
University of Karachi, Pakistan for the facilities pro-
rapid and better solubility with an f2 similarity of vided for above mentioned experiment successfully.
64 as shown in Figure 2, indicating a better dis-
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