doi.org/10.36721/PJPS.2019.32.6.REG.2573-2578.

Formulation, evaluation and in vitro characterization of

gastroretentive floating tablet of diclofenac sodium

Muhammad Qaiser Shehzad1, Taha Nazir2, Saeed-Ur-Rashid Nazir1,

Nida Taha3, Tahir Jamil4 and Muhammad Abdullah Akram4
1
Department of Pharmacy, University of Sargodha, Sargodha, Pakistan
2
Chemical Pathology & Molecular Biology Research Group, Advanced Multiple Inc., Mississauga ON Canada
3
Riphah Institute of Pharmaceutical Sciences, Riphah International University (Lahore Campus), Lahore, Pakistan
4
Department of Pharmaceutics, Facutly of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan

Abstract: Currently a variety of tools and techniques are used to deliver complex medicines. Whereas, certain advanced
methods assure the safety and usefulness by regulating the pharmacokinetic and pharmacodynamic. Thus, we aimed this
study to develop a novel gastro retentive floating tablets. The formulation was designed to provide the desired controlled
and complete release of drug for prolonged period of time. The formulations were evaluated for physical
characterization. The obtained results of hardness (4.6-5.1), friability (0.20-0.43%), weight variation (350 ±2 - 350±5)
and in vitro buoyancy were found within official limits of United Stated Pharmacopoeia (USP). Whereas, the F-7 showed
most optimized intra gastric floating characteristics and exhibited 93.87% release of diclofenac sodium in 9 hours. The
Floating Lag Time of 8 minutes and Total Floating Time ≥12 hours were recorded. In-vitro drug release kinetics
evaluated using the linear regression method was found to follow the Zero Order and Peppas model for the release of
both the drugs. DSC thermograph and FTIR spectra depicted that there was no chemical incompatibility between drugs
and polymers. In conclusion the desgined tablet can be use in clinical practice as model drug. Because, the pre-
compression and post-compression parameters were satisfactory and within desired limits.

Keywords: Telmisartan, mouth disintegrating tablet, extended release profile, response surface methodology.

INTRODUCTION overcome the trouble confronted by some people in order

to silence the voice or blocking during swallowing the
Drug Delivery System (DDS) is the technique or manner tablets. The writer proposed a method that such difficulty
of delivering complex drugs to attain a therapeutic effect can be controlled by offering a grain density of a smaller
in human beings or animals. (Yun et al, 2015) These are amount than 1.0g /ml thus the pill will float on the water
the preparations or devices that permit the introduction of surface. (Nayak et al., 2010).
therapeutically active material in the body to increase its
safety and usefulness by regulating the degree, place and Diclofenac sodium is a NSAID (non - steroidal anti-
time of its release into the body. While administering the inflammatory drugs). Diclofenac Sodium is a simple vinyl
medicine, the dosage must be wisely calculated so that the derivative of acetic acid. It looked like a both flurbiprofen
body can use the drug. This could be attained by a drug and meclofenamate. It decreases fever and inflammation
delivery system which permits for precise dosing. (Tiwari and relieves pain. It is of anthropogenic origin and
et al., 2012) Need of drug delivery systems also have to belongs to the phenyl acetic acid. It belongs to the group
ponder the way in which the drug is metabolized in the of cyclooxygenase (COX) inhibitor on the basis of its
body. For specimen, some drugs broken in the GIT and mechanism of action. It is also categorized in painkillers
can’t be used to administer into the body in such a and anti-inflammatory medicines. Plasma protein binding
manner. Others may be hazardous in large quantities; of diclofenac sodium is 99%. Renal excretion of
therefore the process of release time should be controlled diclofenac sodium accounts for 65% and plasma half-life
to deliver medication safely. The usefulness of the drug is 1-2 hours. (Alzaher et al., 2015). The immediate release
delivery system is affected, by the interval of time it takes tablets of diclofenac sodium which are used to treat the
to get a drug to show its therapeutic effect in the body. primary dysmenorrhea, mild and moderate pain of
Effective new approaches of delivery have the capability rheumatoid arthritis, and arthritis are available.
to decrease the dose and unwanted or undesired effects.
(Jain et al., 2008). Empirical formula: C14H10Cl2NNaO2
IUPAC name: SODIUM [2-[(2, 6-
The idea of FDDS has been discussed in literature in the DICHLOROPHENYL)
initial part of 1968, Davis revealed a technique to AMINO] PHENYL] ACETATE
Molecular weight: 318.14
*Corresponding author: e-mail: [email protected]

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Formulation, evaluation and in vitro characterization of gastroretentive floating tablet of diclofenac sodium

Anti-inflammatory effects of the Diclofenac are supposed to formulate, evaluate and in vitro characterize the
to be due to inhibition of the migration of the leukocyte gastroretentive floating tablet of diclofenac sodium.
and inhibition of the enzymes cyclooxygenases (COX-1
and COX-2), it leads to the prostaglandin’s synthesis
inhibition. It is well absorbed after taking orally. (Taha et
al., 2015). Diclofenac Sodium experiences first-pass
metabolism; the quantity of drug which enters the
circulation is 50 to 60% of the given dose. Peak plasma
concentration is typically reached in 1 hour for
conventional tablets of Diclofenac sodium, the time to
reach peak plasma concentration for delayed release
tablets is 2 hours and for extended release tablets the time
is 5.25 hours. . Also gets absorbed into systemic
circulation by applying topically as a transdermal system
or as a gel; plasma concentrations is very low after topical
application as compared to when orally
administered. (Munjal et al., 2015).

Fig. 2: In vitro drug release profile for diclofenac sodium

of formulations F4, F5, F6& F7 Release Kinetics study

MATERIALS AND METHODS

The research study was conducted in HighTech

Laboratory, University of Sargodha, Pakistan during
January, 2014 to April, 2015. The major instruments
involved in this research were include Hardness tester
(Pharmatest, Germany), FTIR Apparatus (IR Pristage 21
Shimadzu, Japan), DSC Apparatus (Ta 2000 USA),
Fig. 1: Standard calibration curve of diclofenac sodium. Dissolution apparatus (DT 700 erweka Germany), pH
meter (Ionolabwtw series 720), membrane filters
After single dose (50-100 mg) provides pain relief for 8 (Minipore USA) and Sonicator mixer (Elma Germany).
hours. Food can delay the absorption but do not have Whereas, the chemical and reagents Diclofenac Sodium,
effect on the degree of absorption. It has wide distribution HPMC K15M, Cetyl Alcohol, Carnauba wax, Xanthan
in animals., its concentrations in synovial fluid may gum, Sodium Bicarbonate NaHCO3, Magnesium stearate
perhaps exceed from the concentration in plasma. Plasma and Talc were collected from Prim Laboratories Pvt. Ltd,
Protein Binding is about 99%. It mainly undergoes liver Lahore, Pakistan and bought from local pharmaceutical
metabolism through reaction of conjugation and marketed of Lahore, Pakistan.
hydroxylation. Some of the metabolites may also display
anti-inflammatory activity . 65% of it is excreted in urine Study design
and feces and 35% is through bile as metabolites (Singh et We developed the 10 formulations of gastro retentive
al.,2012). Oral preparations: 1–2 hours. (Woodhouse & floating tablet of diclofenac sodium by using different
Wyne, 1987). combinations of polymers and gave the codes to these
formulations from F1 to F10. After the development of
Moreover, it is well-thought to be faster acting and formulations we did evaluation and characterization of
harmless as compared to ibuprofen. It also has activity for formulations from F1 to F10. Evaluation and
longer time as compared to paracetamol. Diclofenac characterization was divided into 3 categories, 1st pre
sodium and potassium are the two salt forms in which compression evaluation, 2nd post compression evaluation
diclofenac is mostly used. Diclofenac sodium and and 3rd compatibility study. In Pre-Compression
potassium have similarity of having same diclofenac base evaluation we evaluated different characteristics of the
but are different from each other in nature and function, powder blend/granules which includes, bulk density,
their dose is same even then these cannot be treated as tapped density, compressibility index, angle of repose and
equivalents. Diclofenac potassium is formulated as hausner’s ratio. After pre-compression evaluation
immediate release, whereas diclofenac sodium is granules were compressed to make tablets and after that
formulated as delayed release. Hence, we aimed this study we did post-compression evaluation which includes, form
2574 Pak. J. Pharm. Sci., Vol.32, No.6, November 2019, pp.2573-2578
 Muhammad Qaiser Shehzad et al

of tablets, tablet dimensions, weight variation, hardness, the required quantities of Cetyl alcohol and carnuba wax
friability, in-vitro buoyancy, in-vitro dissolution and were melted in a china dish of large size on the water
release kinetics. Compatibility between drugs and bath. The previously weighed and properly mixed powder
polymers was also studied by using DSC (Differential blend of drugs, HPMC K15M, Sodium Bicarbonate,
Scanning Calorimetry) and FTIR (Fourier Transform Xanthan Gum was added to the molten Cetyl alcohol and
Infrared Spectroscopy). Carnuba wax to form a semisolid mass. After proper
mixing china dish was cooled after removing from water
bath. The solidified mass was then removed and then it is
passed through the sieve no. 30. At the end magnesium
stearate and talc were added and thoroughly mixed and
then compressed to make tablets.

Pre-compression Evaluation and characterization

Pre-compression assessment of diclofenac sodium
granules was carried out by using following methods:

Angle of repose
The flow properties of granules (before compression) will
be characterized in terms of angle of repose, Carr’s index
Fig. 3: DSC thermograph of diclofenac sodium and Hausner’s ratio. The angle of repose of granules was
measured by the simple funnel method. The weighed
quantity of granules placed in the funnel. (Gambhire et
al.,2007; Funnel’s height was so adjusted that funnel’s tip
was just touching the peak of the cone of the granules.
The granules were freely allowed to flow through the
funnel. The diameter of the cone was measured and then
calculated the angle of repose from the equation given
below. (Yadav et al.,2010)
Tan = h / r
Where, h is the height of the powder/granules cone and r
is the radius.

Bulk and tapped density

Both bulk (BD) and tapped densities (TD) have been
measured. The 2 grams quantity of powder mixture of
each formulation, shaken to break any clumps formed,
was taken in a measuring cylinder of10 ml capacity. After
measuring initial volume of the granules/powder the
cylinder was allowed to fall from the height of 2.5 cm.
(Saravanan et al.,2011)The tapping continued until there
Fig. 4: FTIR spectra of diclofenac sodium is no further changes observed in volume. BD and TD
were calculated by using the following equations
Preparation of the standard curve of diclofenac sodium BD = weight of powder blend / untapped volume of
Solutions of different concentrations were prepared from packing
10 microgram per ml to 115 micrograms per ml by using
ethanol and 0.1N HCl, absorbance was measured for each TD = weight of powder blend / tapped volume of packing
solution at lambda max of 276nm. (Subramaniyan et al., Carr's index
2013). It is a test to assess the ability of the powder to be
compressed or the rate at which it packed down, It is
Preparation of the floating tablets by using melt measured by measuring the BD and TD of powder and
granulation method putting the values in following formula.
Each floating tablet consisting of 100mg diclofenac Carr’s Index = [TD – BD] / TD x 100
sodium was formulated by a conventionally used method
of melt granulation. The compositions of tablet It is frequently used in the pharmaceuticals as an indicator
formulations are listed in the table with their codes. The for the powder’s flow ability. Value of Carr’s Index more
combination of polymers was carefully chosen on the than 25 indicates that the powder has weak flow property,
base of trial preparation. According to each formulation
Pak. J. Pharm. Sci., Vol.32, No.6, November 2019, pp.2573-2578 2575
Formulation, evaluation and in vitro characterization of gastroretentive floating tablet of diclofenac sodium

Table 1: Composition of all of the ten formulations for diclofenac sodium floating tablets

No. Ingredient Formulation (Quantities in mg)

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
1. Diclofenac Sodium 100 100 100 100 100 100 100 100 100 100
2. HPMC K15M 66 66 66 66 66 66 66 66 66 66
3. Carnuba Wax 20 20 30 40 50 60 70 80 90 95
4. Cetyl Alcohol 65 65 55 45 35 30 20 10 0 0
5. Sodium Bicarbonate 0 0 10 20 30 30 30 40 50 60
6. Xanthan Gum 90 90 80 70 60 55 55 45 35 20
7. Magnesium Stearate 6 6 6 6 6 6 6 6 6 6
8. Talc 3 3 3 3 3 3 3 3 3 3
9. Total Weight 350 350 350 350 350 350 350 350 350 350

Table 2: Angle of Repose and Carr’s Index

Flow Angle of repose Carr’s index ( % )

Excellent <25 5-15
Good 25-30 12-16
Fair to passable 30-40 18-21
Poor > 40 23-35
Very Poor 33-38
Extremely Poor >40

and value less than 15, indicates good flow ability of the vitro dissolution study. Selected formulations were F4, F5,
powder. F6, F7. Whereas, the results of FLT and TFT, four
formulations were selected for the testing of in-vitro
Hausner ratio dissolution and drug release and rest of the 6 formulation
Carr index is related to Hausner ratio, further evidence of were rejected due to more FLT or less TFT. Selected
the ability of the flow, by the formula, formulations were F4, F5, F6 and F7.
Hausner ratio = Bulk Volume / Tapped Volume
In-vitro dissolution study was conducted for the selected
RESULT formulationsF4, F5, F6 and F7of diclofenac sodium in
0.1N HCl solution. Study was conducted for 9 hours and
The evaluated for physical characterization of the cumulative drug release at different time intervals was
designed formation shown the hardness (4.6-5.1), calculated. The results are shown in the table 3 & 4. The
friability (0.20-0.43%), weight variation (350 ±2 - 350±5) plot of the cumulative percentage of drug release v/s time
and in vitro buoyancy were found within official limits of (hours) shown in figs. 2, 3 & 4.
United Stated Pharmacopoeia (USP). Whereas, the F-7
showed most optimized intra gastric floating Table 3: Standard calibration curve of diclofenac sodium
characteristics and exhibited 93.87% release of diclofenac
sodium in 9 hours. The Floating Lag Time of 8 minutes Sr. No. Concentration ug/ml Absorbance
and Total Floating Time (TFT) ≥12 hours were recorded. 1. 10 0.108
The time period up to which the tablet remained buoyant 2. 20 0.32
is described as Total Floating Time (TFT). Whereas, the 3. 30 0.532
time required for tablet to rise to the surface and float is 4. 40 0.744
defined as Floating Lag Time (FLT). So, the prepared 5. 50 0.956
tablets were studied for In vitro buoyancy study in 0.1M 6. 70 1.38
HCl at 37°C +0.5. Formulations with low quantity of 7. 90 1.804
sodium bicarbonate took more time to float and the 8. 115 2.334
formulations with large amount of sodium bicarbonate
had very short floating lag time but showed less total Drug release mechanism was determined by putting the
floating time and vice versa. According to the results values of release data into kinetic equations. Formulations
formulations with low floating lag time and having total were found to follow Zero Order, First Order and peppas
floating time more than 12 hours were selected for the in- model. According of drug release profile of Diclofenac
Sodium Formulations F4 followed First Order and Peppas
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 Muhammad Qaiser Shehzad et al

Table 4: In-vitro drug release profile (diclofenac sodium) of formulation F4, F5, F6 & F7

Time (hrs.) F4 F5 F6 F7
0 0.00 0.00 0.00 0.00
1 26.40 14.87 18.27 15.15
2 31.35 18.58 25.43 24.04
3 54.97 23.64 36.80 36.72
4 50.18 33.10 45.81 46.65
5 65.43 44.56 51.73 55.99
6 75.65 59.47 60.81 65.50
7 78.98 70.65 68.15 73.82
8 84.19 75.39 74.93 84.97
9 84.66 81.23 83.07 93.87

Table 5: Model fitting of the release profile of diclofenac sodium using four different models

Formulation Zero Order R2 First Order R2 Higuchi R2 Peppas Value ‘n’

F4 0.8438 0.9876 0.9800 0.9861 0.574
F5 0.9834 0.9299 0.8485 0.9861 0.574
F6 0.9601 0.9867 0.9517 0.9983 0.740
F7 0.9911 0.9577 0.9113 0.9993 0.867

model, F5 followed Zero Order and Peppas model, F6 mixtures of drugs. Infrared spectra of diclofenac sodium
followed Peppas mode and F7 release the drug with zero exhibited characteristic peaks at 1581.63cm-1 due to the-C
order kinetics and also followed Peppas model. The value =O stretching from the carboxyl ion & at 759.95cm -1
of ‘n’ was in the range 0.574- 0.867 which depicts drug due to C-Cl expansion. Carnauba wax offered distinct
release by anomalous transport and polymer erosion. peaks in 2860.43 to 2920.23cm-1 due to CH2 stretching
Thus, our finding are in line with Gambhire et al., (2) who vibrations, in 2847.8 cm-1 because C-CH3 stretching
develop an in vitro evaluation of an oral floating matrix vibrations while the signal resulting from the carboxyl
tablet formulation. group appeared in 1722.43cm-1. Cetyl alcohol shows C=O
stretching vibration at 1639.49, the peak in 1018.41cm
Moreover, the DSC has been used to detect any due to C-OH Stretching vibration. Xanthan gum have the
incompatibility in the formulations due to drug polymer peaks of C-CH2, C-OH, C=O at the range of 2893.22,
interaction and thermo grams of pure drugs, pure 1037.7, 1612.49 to 1722.43 respectively. Thus, there was
polymers and of formulations are shown in figs. 3. In the no any chemical reaction with the diclofenac sodium and
scheme of DSC heat of pure diclofenac Sodium showed polymers reported. (Taha et al., 2015)
endothermic peak at 307Co.
CONCLUSION
DISCUSSION
In conclusion, the gastro-retentive effervescent floating
The effects of various components and its focus on the diclofenac sodium tablet may be developed to use in
release of drugs is studied. Our finding are substantiated actual clinical practice. The floating tablets were prepared
by Alzaher et al., (1) who reported the formulations with by incorporating different combinations of polymers.
equal amount of drugs, main polymer, lubricants and Moreover, the findings of pre-compression and post-
glidant. compression were also satisfactory and within the official
limits. In addition of that, the F-7 showed the most
The value of ‘n’ in aforesaid study was in the range 0.574- promising results. That can potentially be developed to
0.867 which depicts drug release by anomalous transport get more desirable properties and drug release profile.
and polymer erosion. Thus, our finding are in line with
Gambhire et al., (2) who develop an in vitro evaluation of ACKNOWLEDGMENT
an oral floating matrix tablet formulation.
The authors acknowledge the kind support of, Dr. Sher
Additionally, to make sure of the quality and quantity Muhammad, Deputy Manager High Tech Lab., Associate
analysis by FTIR a mixture of pure and blended polymers Professor and Chairman, Department of Chemistry,
used in the composition. (Munjal et al., 2015) The IR University of Sargodha, Pakistan. Munawar Shahid Bhati,
spectra of pure drugs and pure polymers compared with Production Manager, Prime Laboratories (Pvt) Ltd., 9.5
the infrared spectra of the different formulas Polymer KM Lahore Sheikhupura Road, Lahore, Pakistan
Pak. J. Pharm. Sci., Vol.32, No.6, November 2019, pp.2573-2578 2577
Formulation, evaluation and in vitro characterization of gastroretentive floating tablet of diclofenac sodium

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