Malleswari et.

al

Indian Journal of Research in Pharmacy and Biotechnology

ISSN: 2321-5674(Print) ISSN: 2320 3471(Online)

Comparative in-vitro dissolution study of five brands of Diclofenac sodium delayed

release tablets in QbD environment
V Malleswari Bai*1, M Prasada Rao1, M Chandana1, K Naga Harini1, B Naga Deepthi1, K Thirumala Devi1,
2
P Lakashmana Rao1, Vinay U rao and J Naga raja1
1. Department o f Pharmaceuitical Analysis, Medarametla Anjamma Masthanrao College of Pharmacy, Narasarao
Pet, Guntur district, Andhra Pradesh, India.
2. Institutes of Pharmaceutical Sciences, Hyderabad-500049
*Corresponding author: E.Mail:malleswari.v4@gmail.com
ABSTRACT
Diclofenac sodium tablets are available as delayed release tablets in the market. Delayed release
tablets are typically produced by coating the tablet with enteric coating polymers. These polymers provide
the resistance of drug release in acidic environment of stomach and allow the drug to be released in
alkaline environment of the intestine. A large number of enteric polymers are available which provide
excellent protection to drug release in acidic environment. However, each polymer dissolves at different
alkaline pH. For e.g. Eudragit L-100 dissolves at pH 6 and above while Eudragit S-100 dissolves at pH
6.5 and above. HPMC Phthalate P5.5 dissolves at pH 5.5 and above while HPMC Phthalate P dissolves at
pH 6 and above. Hence, for the same drug the bioavailability can subtly but significantly change based on
which enteric polymer is used to provide the delayed release. The aim of the current work was to
comparatively evaluate five brands of Diclofenac sodium enteric coated tablets and determine which
brands may be equivalent to each other based on in vitro testing. Comparative dissolution profile testing
was carried out in pH 5.5, pH 6 and pH 6.8 buffers. It was determined that brand 1 and 5 are equivalent to
each other while brands 2, 3 and 4 are equivalent to each other. Similarity factor f2 was used for
comparing the dissolution profiles. Alcohol dumping studies indicated that only brand 1 was able to
withstand the enteric effect at 40% level of alcohol. All other marketed brands fail the alcohol dumping
test. This indicates that patients may have to counsel not to concomitantly consume alcohol while on
Diclofenac sodium delayed release tablets.
Key words: Diclofenac sodium, Quality by design (QbD), Delayed release, Dissolution test
INTRODUCTION
Quality by Design (QbD) is a concept first
outlined by well-known quality expert Joseph M
Juran in various publications, most notably Juran on
Quality by Design. Juran believed that quality could
be planned, and that most quality crises and problems
relate to the way in which quality was planned in the
first place. While Quality by Design principles has
been used to advance product and process quality in
every industry, and particularly the automation
industries, they have most recently been adopted by
the U.S Food and Drug administration (FDA) as a
vehicle for the transformation of how drugs are
discovered,
developed,
and
commercially
manufactured (Juran, 1992).
MATERIALS AND METHODS
Development of a predictive dissolution method:
The effects of dissolution medium pH, stirring speed,
volume of the dissolution medium, type of apparatus
used were systemically evaluated to develop the
predictive dissolution method

using USP apparatus 2 .Effect of dissolution medium

pHof both the innovator product and the four brands
were subjected to dissolution testing using USP
apparatus 2 at 50 rpm in 900 mL of various media
including water, 0.1 N HCl, pH 5.5 phosphate buffer,
and pH 6.8 phosphate buffer. The drug release of the
marketed samples in comparison with the innovator at
different time intervals was obtained in all the
mediums. The similarity factor of the brands using
innovator product as the reference is calculated
Effect of dissolution medium volume: The drug
release of innovator products and all the marked
brands was evaluated using pH 1.2(0.1N HCl)
dissolution medium volumes of1000ml and 500ml.
The stirring speed was 50 rpm in each case. The drug
release profile of the marketed samples in comparison
with the innovator product at various time intervals
were obtained in all two volumes. The similarity
factor of the brands using innovator product as the
reference is calculated

Effect of dissolution medium: An initial attempt at

developing the discriminating dissolution method that
would be predictive of in vivo performance was made

Effect of stirring speed: Dissolution testing of all the

marketed samples and the innovator product was
conducted at25, 50, 75, and 100 rpm in 900 mL of pH
1.2(0.1NHCl) dissolution medium. The similarity

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factor of the brands using innovator product as the

reference is calculated

Effect of type of dissolution apparatus: Dissolution

testing of all the marketed samples and the innovator
product was conducted using both USP1 (Basket) and
USP2 (Paddle) apparatus in 900ml of pH
1.2(0.1NHCl) dissolution medium. The drug release
profiles of all the marketed samples in comparison
with the innovator product at various time intervals
were obtained. The similarity factor of the brands
using innovator product as the reference is calculated

QbD development process includes:

Begin with the target product profile that
describes the use, safety and efficacy of the
product.
Defining a target quality profile that will be
used by formulators and process engineers as
a quantitative surrogate for aspects of clinical
safety and efficacy during product
development.
Gather relevant prior knowledge about the
substance, potential excipients and process
operation.
Design a formulation and identify the quality
attributes to the final product that must be
controlled to meet the target product quality
profile.
Design a manufacturing process to produce a
final product having this critical material
attributes.
Identify the critical process parameters and
raw material attributes that must be controlled
to achieve these critical material attributes of
the final product.
Establish a control strategy for the entire
process that may include input material
controls, process controls and monitors design
space around individual or multiple unit
operation and/ or final product tests.
Continually monitor and update the process to
assure consistent quality.

ISSN: 2321-5674(Print) ISSN: 2320 3471(Online)

Dissolution is the process by which a solid

solute enters a solution, and is characterized
by rate (amount dissolved by time).
In the pharmaceutical industry, it may be
defined as the amount of drug substance that
goes into solution per unit time under
standardized conditions of liquid/solid
interface,
temperature
and
solvent
composition.
Dissolution is the quality control measure and
potential to provide in sight into the in vivo
performance of the drug product.
In vitro release test that predicts the drug in
vivo would be optimal and highly desirable.
A variety of designs of apparatus for
dissolution testing have been proposed and
tested, varying from simple beaker with stirrer
to complex systems.
Different
apparatus,
procedures
and
techniques are required for different dosage
forms because of significant differences in
formulation design and the physicochemical
properties of the drugs.
Dissolution tests have been developed for
various drug delivery systems including
immediate release solid dosage forms, several
controlled release solid dosage forms and
many novel and special dosage forms.

Most of the tests with recommended apparatus and

other specifications are now available as compendial
standards in Pharmacopoeias and are used in
pharmaceutical analysis and drug development for the
various drug delivery systems.

Dissolution testing and drug release:

Dissolution testing has been widely used as
the primary tool to evaluate drug release

RESULTS AND DISCUSSION

Five brands of Diclofenac sodium delayed
release tablets 50 mg were procured from the market
and subjected to assay and comparative dissolution
profile testing as per USP guidelines for determining
in vitro equivalence of modified release products.
Assay of Diclofenac sodium delayed release tablets:
Twenty tablets were weighed and crushed using
mortar and pestle. Quantity of powder equivalent to
100 mg of Diclofenac sodium was weighed accurately
and transferred to 100 ml volumetric flask.
Approximately 70 ml of methanol AR grade was
added and syndicated for 15 minutes. The volume was
made up to 100 ml with methanol and filtered. From
the clear filtrate and aliquot equivalent to 100 ppm
was pipette out and transferred to 10 ml volumetric
flask. The volume was made up to 10 ml with
Methanol (10 g/ml solution). The absorbance of this

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November December 2013

Quality by Design for drug release

Two primary aspects:
1. Clinical relevance of release and stability
specifications
2. Correlation between process parameters
and ability to achieve specifications (and
therefore remain clinically relevant)

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solution was measured on UV spectrophotometer at

276 nm wavelength. The drug content was calculated
by simultaneously measuring the absorbance of a
standard 10 g/ml solution of Diclofenac sodium. The
assay values for all five brands are given in Table 1.
Disintegration test for Enteric coated tablets (IP):
The DT test for enteric coated tablets as described in
IP was performed for 6 tablets of each brand and it
was observed that all brands pass this test
Comparative dissolution testing in 0.1N HCl: It is
mandatory for all delayed release products to show <
10% drug release in 0.1N HCl when in vitro
dissolution testing is performed for 2 hours in this
medium. The results for the dissolution testing of the
5 brands are given in Table 2 and shown in Figure.1.
All five brands passed the criteria of <10% in two
hours in pH 1.2 medium.
Comparative dissolution testing in pH 5.5: pH 5.5
simulates the duodenum and upper intestinal portion.
Comparative dissolution testing was conducted in pH
5.5 acetate buffer for 1 hour (Figure.2)
The dissolution profiles were statistically
compared by calculating the similarity factor (f2). The
f2 factor for brand 2, 3, 4 and 5 was calculated by
comparing with brand 1. Only brand 5 showed f2 >
50. Hence this may be considered as equivalent to
brand 1 for dissolution profile testing in pH 5.5. The
f2 factor for brand 1, 3, 4 and 5 was calculated by
comparing with brand 2. Brand 3 and 4 showed f2 >
50. Hence these may be considered as equivalent to
brand 2 for dissolution profile testing in pH 5.5. The
f2 factor for brand 1, 2, 4 and 5 was calculated by
comparing with brand 3. Brand 5 showed f2 > 50.
Hence this may be considered as equivalent to brand 3
for dissolution profile testing in pH 5.5. The f2 factor
for brand 1, 2, 3 and 5 was calculated by comparing
with brand 4. Brand 2 showed f2 > 50. Hence this may
be considered as equivalent to brand 4 for dissolution
profile testing in pH 5.5. The f2 factor for brand 1, 2,
3 and 4 was calculated by comparing with brand 5 as
standard. Only brand 1 showed f2 > 50. Hence this
may be considered as equivalent to brand 5 for
dissolution profile testing in pH 5.5.
Comparative dissolution testing in pH 6.0: pH 6.0
simulates the duodenum and upper intestinal portion.
Comparative dissolution testing was conducted in pH
6.0 Phosphate buffer for 1 hour. (Figure.3)

ISSN: 2321-5674(Print) ISSN: 2320 3471(Online)

comparing with brand 1. Only brand 5 showed f2 >

50. Hence this may be considered as equivalent to
brand 1 for dissolution profile testing in pH 6.0. The
f2 factor for brand 1, 3, 4 and 5 was calculated by
comparing with brand 2. Brand 3 and 4 showed f2 >
50. Hence these may be considered as equivalent to
brand 2 for dissolution profile testing in pH 6.0. The
f2 factor for brand 1, 2, 4 and 5 was calculated by
comparing with brand 3. Brand 2 and 5 showed f2 >
50. Hence these may be considered as equivalent to
brand 3 for dissolution profile testing in pH 6.0. The
f2 factor for brand 1, 2, 3 and 5 was calculated by
comparing with brand 4. Brand 2 and 3 showed f2 >
50. Hence these may be considered as equivalent to
brand 4 for dissolution profile testing in pH 6.0. The
f2 factor for brand 1, 2, 3 and 4 was calculated by
comparing with brand 5. Brand 1 and 3 showed f2 >
50. Hence these may be considered as equivalent to
brand 5 for dissolution profile testing in pH 6.0.
Comparative dissolution testing in pH 6.8: pH 6.8
simulates the middle and lower portion of the gut.
Comparative dissolution testing was conducted in pH
6.0 Phosphate buffer for 1 hour. (Figure.4).
The dissolution profiles were statistically
compared by calculating the similarity factor (f2). The
f2 factor for brand 2, 3, 4 and 5 was calculated by
comparing with brand 1. Brand 2 and 4 showed f2 >
50. Hence these may be considered as equivalent to
brand 1 for dissolution profile testing in pH 6.8. The
f2 factor for brand 1, 3, 4 and 5 was calculated by
comparing with brand 2. Brand 3 and 4 showed f2 >
50. Hence these may be considered as equivalent to
brand 2 for dissolution profile testing in pH 6.8. The
f2 factor for brand 1, 2, 4 and 5 was calculated by
comparing with brand 3. Brand 1 and 5 showed f2 >
50. Hence these may be considered as equivalent to
brand 3 for dissolution profile testing in pH 6.8. The
f2 factor for brand 1, 2, 3 and 5 was calculated by
comparing with brand 4. Brand 2 and 5 showed f2 >
50. Hence these may be considered as equivalent to
brand 4 for dissolution profile testing in pH 6.8. The
f2 factor for brand 1, 2, 3 and 4 was calculated by
comparing with brand 5. Brand 1, 2 and 3 showed f2 >
50. Hence these may be considered as equivalent to
brand 5 for dissolution profile testing in pH 6.8.

The dissolution profiles were statistically

compared by calculating the similarity factor (f2). The
f2 factor for brand 2, 3, 4 and 5 was calculated by

The multimedia dissolution study indicates

that the differences in the rate and extent of
dissolution between different brands are significantly
more at pH 5.5 and pH 6 than at pH 6.8. This may
most likely be due to the fact that each brand may
have been coated with enteric materials of different
chemistries having different solubility profiles in

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Indian Journal of Research in Pharmacy and Biotechnology

alkaline pH. For e.g. the reported solubility of

Eudragit L100 is pH 6 and above while that of
Eudragit L100-55 is pH 5.5 and above. Consequently,
tablets coated with L-100-55 will show significantly
faster and more complete dissolution at pH 5.5 as
compared to Eudragit L-100. All pH dependent
enteric polymers completely dissolve at pH 6.8 and
above. Hence the difference between the brands is
significantly reduced in case of dissolution profile
testing in pH 6.8 buffer.
In order to simulate the way the dosage form is
exposed to pH change in vivo, dissolution profile
testing for all brands was conducted by using the in
situ pH change method. The in situ pH change method
of dissolution testing indicates that all five brands
achieve > 80% release within 30 minutes of reaching
the pH 6.8. However, dissolution profiles for Brand 1
and brand 5 are significantly faster at pH 6 than those
of brands 2, 3 and 4. Hence, from this study it may be
predicted that Brands 1 and 5 may show therapeutic
equivalence to each other while brands 2, 3 and 4 may
be equivalent to each other. But brand 1 and 5 may
not show therapeutic equivalence to brands 2, 3 and
4.(Figure.7).

different solubility profiles in commonly used

solvents. The probability that this may affect the
intended release profile in vivo is very genuine if we
consider that patients may consume alcohol when
under treatment with modified release products. The
solubility profile of the polymer in alcohol may
adversely affect the release rate of the drug from the
dosage form and the actual drug release may be
entirely different from the intended release.
Hence, the US FDA in its latest guidelines has
mandated that the alcohol dumping studies should be
carried out for modified release products in order to
demonstrate that the dosage form is able to perform
within its specified standards even in presence e of
significant levels of alcohol. For the five marketed
brands of Diclofenac sodium delayed release tablets, a
comparative alcohol dumping study was performed in
0.1N HCl without alcohol, and 0.1N HCl with 5%,
10% 20% and 40% v/v of alcohol respectively. The
dissolution profile testing was carried out for two
hours. The study indicates that only Brand 1 is able to
maintain the enteric effect of < 10% release in acidic
pH even in presence of 40% alcohol. All other brands
fail the alcohol dumping test at 40% level of alcohol.
Brand 2 fails the test even at 10% and 20% level of
alcohol. (Figure.8).

Alcohol dumping study: For modified release

products, different types of polymers are used to get
the same kind of effect. Each of these polymers has
Table.1. Assay values for all five Brands of Diclofenac sodium 50 mg delayed release tablets
BRANDS
% Assay

Brand 1
98.76

Brand 2
99.27

Brand 3
97.54

Brand 4
98.04

Brand 5
97.56

Table.2.Comparative dissolution profile testing in 0.1N Hcl

Time

Brand1

Brand2

Brand3

Brand4

Brand5

0
30
45
60
120

0
2.78
5.8
7.9
9.17

0
1.45
3.55
5.07
6.17

0
2.87
4.07
6.27
6.59

0
2.87
3.09
4.13
5.87

0
1.56
2.34
4.09
4.35

Figure.1. Dissolution profiles for 5 brands of Diclofenac

sodium delayed release tablets in 0.1N HCl

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Figure.2.Comparative dissolution profile of five brands in

ph 5.5

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ISSN: 2321-5674(Print) ISSN: 2320 3471(Online)

Figure.3.Comparative Dissolution Profile In Ph 6.0

Phosphate Buffer

Figure.4.Comparative Dissolution Profile In Ph 6.8

Phosphate Buffer

Figure.5. Comparative Dissolution Profile In Ph 6.0

Phosphate Buffer

Figure.6.Comparative Dissolution Profile In Ph 6.8

Phosphate Buffer

Figure.7. Dissolution profile by in situ ph change method

Figure.8.Alcohol Dumping study for Diclofenac sodium

delayed release tablets market brands

SUMMARY AND CONCLUSION

dissolves at pH 5.5 and above while HPMC Phthalate

P dissolves at pH 6 and above. Hence, for the same
drug the bioavailability can subtly but significantly
change based on which enteric polymer is used to
provide the delayed release.

Diclofenac sodium tablets are available as

delayed release tablets in the market. Delayed release
tablets are typically produced by coating the tablet
with enteric coating polymers. These polymers
provide the resistance of drug release in acidic
environment of stomach and allow the drug to be
released in alkaline environment of the intestine. A
large number of enteric polymers are available which
provide excellent protection to drug release in acidic
environment. However, each polymer dissolves at
different alkaline pH. For e.g. Eudragit L-100
dissolves at pH 6 and above while Eudragit S-100
dissolves at pH 6.5 and above. HPMC Phthalate P5.5

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The aim of the current work was to

comparatively evaluate five brands of Diclofenac
sodium enteric coated tablets and determine which
brands may be equivalent to each other based on in
vitro testing. Comparative dissolution profile testing
was carried out in pH 5.5, pH 6 and pH 6.8 buffers. It
was determined that Brand 1 and 5 are equivalent to
each other while brands 2, 3 and 4 are equivalent to

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Indian Journal of Research in Pharmacy and Biotechnology

ISSN: 2321-5674(Print) ISSN: 2320 3471(Online)

each other. Similarity factor f2 was used for

comparing the dissolution profiles.

alcohol while on Diclofenac sodium delayed release

tablets.

Alcohol dumping studies indicated that only

brand 1 was able to withstand the enteric effect at
40% level of alcohol. All other marketed brands fail
the alcohol dumping test. This indicates that patients
may have to counsel not to concomitantly consume

ACKNOWLEDGEMENT
The authors are grateful thanks to Indian
Pharmaceutical Sciences, Arabindo pharma lim,
EMCO industries-hyd, FMC-US, Ashaland specialty
chemicals-US for providing gift samples of
Diclofenac Sodium.

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Mogun H, Schneeweiss S: Cardiovascular outcomes
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5. Graham DJ: COX-2 inhibitors, other NSAIDs, and
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