Ijrpb 1(6) 2 v Malleswari Page 772-777

Malleswari et.al Indian Journal of Research in Pharmacy and Biotechnology ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online)

IJRPB 1(6) www.ijrpb.com November – December 2013 Page 772

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

release tablets in QbD environment V Malleswari Bai*

1, M Prasada Rao

1, M Chandana

1, K Naga Harini

1, B Naga Deepthi

1, K Thirumala Devi

1,

P Lakashmana Rao1, Vinay U rao

2 and J Naga raja

1

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:[email protected]

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

Effect of dissolution medium: An initial attempt at

developing the discriminating dissolution method that

would be predictive of in vivo performance was made

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 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



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.

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)

Dissolution testing and drug release:

Dissolution testing has been widely used as

the primary tool to evaluate drug release

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.

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 µg/ml solution). The absorbance of this



solution was measured on UV spectrophotometer at

276 nm wavelength. The drug content was calculated

by simultaneously measuring the absorbance of a

standard 10 µg/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


comparing with brand 2. Brand 3 and 4 showed f2 >

50. Hence these may be considered as equivalent to



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.


simulates the duodenum and upper intestinal portion.


6.0 Phosphate buffer for 1 hour. (Figure.3)




comparing with brand 1. Only brand 5 showed f2 >

50. Hence this may be considered as equivalent to

















brand 5 for dissolution profile testing in pH 6.0.


simulates the middle and lower portion of the gut.


6.0 Phosphate buffer for 1 hour. (Figure.4).




















comparing with brand 5. Brand 1, 2 and 3 showed f2 >


brand 5 for dissolution profile testing in pH 6.8.

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



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).

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

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).

Table.1. Assay values for all five Brands of Diclofenac sodium 50 mg delayed release tablets BRANDS Brand 1 Brand 2 Brand 3 Brand 4 Brand 5

% Assay 98.76 99.27 97.54 98.04 97.56

Table.2.Comparative dissolution profile testing in 0.1N Hcl Time Brand1 Brand2 Brand3 Brand4 Brand5

0 0 0 0 0 0

30 2.78 1.45 2.87 2.87 1.56

45 5.8 3.55 4.07 3.09 2.34

60 7.9 5.07 6.27 4.13 4.09

120 9.17 6.17 6.59 5.87 4.35

Figure.1. Dissolution profiles for 5 brands of Diclofenac

sodium delayed release tablets in 0.1N HCl

Figure.2.Comparative dissolution profile of five brands in

ph 5.5



Figure.3.Comparative Dissolution Profile In Ph 6.0

Phosphate Buffer


Phosphate Buffer

Figure.5. Comparative Dissolution Profile In Ph 6.0

Phosphate Buffer


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

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

Page 776



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.

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.

REFFERECES

1. Juran JM, Juran on Quality by Design, The Free

Press, A Division of Macmillan, Inc., New York,

1992, 407-425

2. Kearney PM, Baigent C, Godwin J, Halls H,

Emberson JR, Patrono C: Do selective cyclo-

oxygenase-2 inhibitors and traditional non-steroidal

anti-inflammatory drugs increase the risk of

atherothrombosis? Meta-analysis of randomised trials,

BMJ, 3, 2006, 1302

3. Solomon DH, Avorn J, Sturmer T, Glynn RJ,

Mogun H, Schneeweiss S: Cardiovascular outcomes

in new users of coxibs and Nonsteroidal anti-

inflammatory drugs: high-risk subgroups and time

course of risk, Arthritis Rheum, 54(5), 2006, 1378-

89.

4. FitzGerald GA, Patrono C, The coxibs, selective

inhibitors of cyclooxygenase-2, N Engl J Med, 345(6),

2001, 433-42.

5. Graham DJ: COX-2 inhibitors, other NSAIDs, and

cardiovascular risk: the seduction of common sense,

JAMA, 296(13), 2006, 1653-6.

6. Brater DC, Renal effects of cyclooxygyenase-2-

selective inhibitors, J Pain Symptom Manage, 23(4

Suppl), 2002, 15-20.

7. Sigma Aldrich Gan TJ: Diclofenac: an update on its

mechanism of action and safety profile, Curr Med

Res Opin, 26(7), 2010, 1715-31.

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