evaluation of carnauba wax in sustained release … eziuzo.pdf · carnauba, also called brazilwax...

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EVALUATION OF CARNAUBA WAX

A THESIS SUBMITTED TO THE DEPARTMENT OF

BIOLOGICAL

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OKAFO SINODUKOO EZIUZO

EVALUATION OF CARNAUBA WAX IN SUSTAINED

DICLOFENAC SODIUM TABLET FORMULATION

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A THESIS SUBMITTED TO THE DEPARTMENT OF BIOCHEMISTRY

BIOLOGICAL SCIENCES, UNIVERSITY OF NIGERIA, NSUKKA�

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SUSTAINED RELEASE

TABLET FORMULATION.

BIOCHEMISTRY, FACULTY OF

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TITLE PAGE

EVALUATION OF CARNAUBA WAX IN SUSTAINED RELEASE DICLOFENAC SODIUM TABLET

FORMULATION.

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DEDICATION

This work is dedicated to my lovely wife, Chinenye, my children

Dilichukwu, Chimelumunma, Eziuzo and Daluchukwu.

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DECLARATION

We certify that OKAFO SINODUKOO EZIUZO; a postgraduate student in the department of

Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria, Nsukka, has

completed the requirements for the award of the Degree of Master of Pharmacy in

Pharmaceutical Technology and Industrial Pharmacy.

The research work reported in this dissertation is original and has not been submitted

in support of an application for another degree or qualification of this or any other

University.

…………………………………………… ………………………………………

Dr Jacob O. Onyechi Prof G. C. Onunkwo

(Supervisor) (Head of Department)

………………………………………………………………

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(External Examiner)

ACKNOWLEDGEMENT

I thank the Almighty God for the gift of life and the enablement to finish this project.

I wish to express my profound gratitude to my supervisor, Dr Jacob O. Onyechi, for his

assistance and guidance throughout the duration of the program.

I also wish to acknowledge the efforts of the Laboratory and Office staff of the Department of

Pharmaceutical Technology and Industrial Pharmacy especially Emeka Okeh.

Pharm Abali Okolie’s, assistance during the analysis of data was highly appreciated.

The efforts of the management and staff of Pauco Pharmaceutical Industries Nigeria Limited

Awka, Anambra state cannot go unnoticed especially the Managing Director/Chairman, Chief

Paul Okafor, the Superintendent Pharmacist, Pharm Emeka Okpana and the Quality Control

Officer, Mrs Chinwe Chukwurah for allowing me to use their equipment such as DBK

Dissolution Test Apparatus and DBK Ultra Violet Spectrophotometer.

Last but not the least, Mrs. Chinenye, Dilichukwu, Chimelumunma, Eziuzo and Daluchukwu

Okafo, are appreciated for their encouragement and peace of mind at home.

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TABLE OF CONTENTS

TITLE PAGE………………………………………………………………………………….i

DEDICATION…………………………………………………………………………………..ii

DECLARATION………………………………………………………………………………..iii

ACKNOWLEDGEMENT……………………………………………………………………….iv

TABLE OF CONTENTS ………………………………………………………..........................v

LIST OF FIGURES ……..……………………………………………………………………….x

LIST OF TABLES……………………………………………………………………………….xi

ABSTRACT…………………………………………………………………………………….xiii

CHAPTER ONE

1.0: INTRODUCTION

1.1: Sustained release tablets……………………………………………………………………1

1.1.1: Formulation of sustained – release tablets………………………………………………1

1.1.2: Methods of achieving sustained – release………………………………………………..2

1.1.2.1: Diffusion – controlled release…………………………………………………………….3

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1.1.2.2: Dissolution – controlled release……………………………………………..……………4

1.1.3: Benefits of sustained – release tablets…………………………………….......……………4

1.1.4: Disadvantages of sustained – release tablets………………………………………………5

1.1.5: Mechanism of drug release from wax matrices……………………………………………5

1.2: Carnauba wax………………………………………………………………………………6

1.2.1: Composition………………………….……………………………………………………6

1.2.2: Physicochemical properties………..……………………………………………………...6

1.2.3: Uses……………………………………………………………………………..…………7

1.3: Arthritis………………………………………………………………………………………7

1.3.1: Signs and Symptoms……………………………………………………………………….8

1.3.2: Treatment………………………………………………………………………………….9

1.3.2.1: Non Steroidal Anti Inflammatory Drugs (NSAIDs)…………………………….............9

1.4: Diclofenac Sodium…………………………………………………………………………10

1.4.1: Therapeutic Indication, Dose and Therapeutic Index……………………………………11

1.4.2: Pharmacokinetic Properties of Diclofenac Sodium………………………………………11

1.4.2.1: Absorption …………………………………………………..………………………....11

1.4.2.2: Distribution……………………………………………………………………………..12

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1.4.2.3: Metabolism……………………………………………………………………………..12

1.4.2.4: Excretion………………………………………………………………………………..13

1.5: Melt Granulation……………………………………………………………………………13

1.5.1: Uses………………………………………………………..………………………….…14

1.5.2: Advantages of Melt Granulation…………………………………………………………14

1.5.3: Disadvantages of Melt Granulation………………………………………….……………14

1.5.4: Dissolution Test…………………………………………………………………………..15

CHAPTER TWO

2.0: MATERIALS AND METHODS

2.1: Materials…………………………………………………………………………………….17

2.2: Methods…………………………………………………………………………………….17

2.2.1: Preformulation Studies……………………………………………………………………17

2.2.2: Preparation of Diclofenac Sodium granules….......................……………………………17

2.2.3: Compression of Diclofenac Sodium granules....................................………………...20

2.2.4: Dissolution test studies ...........................................................…….……………………20

2.2.5: Friability Test.…………………………………………………………………………21

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2.2.6: Uniformity of Weight test...………………………………………………………..21

2.2.7: Determination of Crushing Strength of Batches DS1 – DS6 of Diclofenac Sodium

tablets...........................................................................................................................................21

2.2.8: Melting point determination.……………………………………………………………..22

2.2.9: Preparation of Buffer Solutions…………………………………………………………22

2.2.9.1: Preparation of Buffer Solution of pH 1.2………………………………………………22

2.2.9.2: Preparation of Phosphate Buffer Solution of pH 6.8…………………………………..23

2.2.10: Analysis of Data…....……………………………………………………………..........23

2.2.11: Assay of active ingredients .............................................................................................25

2.2.12: Measurement of tablet thickness and diameter..................................................................25

CHAPTER THREE

3.0: RESULTS AND DISCUSSION

3.1: Some physical properties of batches of diclofenac sodium tablet .........................………...26

3.2: In – vitro preformulation studies…................................……………………………………28

3.3: Release characteristics..........................…………………………………………………….28

3.3.1: Kinetics of drug release...............………………………………………………………..38

3.3.2: Mechanisms of drug release..........................................................……………………….46

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CHAPTER FOUR

4.0: Summary, Conclusion and Recommendations

4.1: Summary and Conclusion…………………………………………………………………57

4.2: Recommendations………………………………………………………………………...58

4.3: References………………………………………………………………………………….59

APPENDICES…………………………………………………………………………….…...64

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LIST OF FIGURES

Fig. 1: Sequential release of diclofenac sodium from batches DS1, DS2, DS2’, DS3, DS4, DS5,

DS6 and DSC ……………………………...…………………………………………………….29

Fig. 2: Sequential release of diclofenac sodium from batch DS 1 tablets in aqueous media

of pH 1.2 and phosphate buffer, pH 6.8…………………………………………….......30

Fig. 3: Sequential release of diclofenac sodium from batch DS 2 tablets……………………...31

Fig. 4: Sequential release of diclofenac sodium from batch DS 2’ tablets…………………….32

Fig. 5: Sequential plot of the release of diclofenac sodium from batch DS 3 tablets………….33



Fig. 8: Sequential release of diclofenac sodium from batch DS 6 tablets……………………36

Fig. 9: Sequential plot of the release of diclofenac sodium from batch DS C tablets…………37

Fig. 10: Higuchi plot of the release of diclofenac sodium from batch DS 1 tablets………….....38

Fig. 11: First order plot of the release of diclofenac sodium from batch DS 2 tablets…………39

Fig. 12: First order plot of the release of diclofenac sodium from batch DS 2’ tablets…………40

Fig. 13: First order plot of the release of diclofenac sodium from batch DS 3 tablets………….41

Fig. 14: First order plot of diclofenac sodium from batch DS 4 tablets………………………42

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Fig. 17: First order plot of the release of diclofenac sodium from batch DS C tablets…………45

Fig. 18: Korsmeyer – Peppas plot f the release of diclofenac sodium from batch DS 1 tablets...47

Fig. 19: Korsmeyer – Peppas plot of the release of diclofenac sodium from batch DS 2 tablets.48

Fig. 20: Korsmeyer – Peppas plot of the release of diclofenac sodium from batch DS 2’

tablets…………………………………………………………………………………………….49

Fig. 21: Korsmeyer – release plot for the release of diclofenac sodium from batch DS 3

tablets…........................................................................................................................................50

Fig. 22: Korsmeyer – Peppas plot of the release of diclofenac sodium from batch DS 4

tablets…………………………………………………………………………………………..51

Fig. 23: Korsmeyer – Peppas plot of the release of diclofenac sodium from batch DS 5

tablets………………………………………………..………………………….52

Fig. 24: Korsmeyer – Peppas plot of the release of diclofenac sodium from batch DS 6...53

Fig. 25: Korsmeyer – release plot for the release of diclofenac sodium from batch DS C

tablets....................................................................................................................................54

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LIST OF TABLES

Table 1: Formula for preparing 81.2g of Diclofenac sodium granules…....................................19

Table 2: Uniformity of tablet weight………………………………............................................21

Table 3: Diffusion exponent and solute release mechanism for cylindrical shape......................25 Table 4: Some physical properties of batches of diclofenac sodium tablets..............................26

Table 5: Summary of pharmacokinetic parameters for the release of Diclofenac sodium from

batches of Diclofenac sodium tablets…............................................................………..55

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ABSTRACT

Matrix granules of Diclofenac sodium were formed by melt granulation using different

concentrations of carnauba wax (24.6, 30.8, 36.9, 43.1, 49.3 and 73.9 %). The respective matrix

granules were compressed directly into tablets using a single station Manesty tableting machine.

Dissolution test studies were done for the seven batches (DS 1, DS 2, DS 2’, DS 3, DS 4, DS 5

and DS 6) and DS C, a commercially available brand (Voltaren RetardR) used as the control for

12 hours (2hours at pH 1.2 and 10hours at pH 6.8). The mean (± s.d.) percent of drug release

from Diclofenac sodium matrix tablets after 12 hours from batches DS 1, DS 2, DS 2’, DS 3, DS

4, DS 5, DS 6 and DS C are 23.86 ± 0.06, 31.08 ± 0.10, 52.03 ± 0.00, 95.94 ± 0.31, 55.09 ± 0.08,

70.78 ± 0.93, 73.00 ± 0.15 and 62.28 ± 2.08% respectively

. The mechanism of release of Diclofenac Sodium in simulated intestinal fluid was anomalous

(non – Fickian) diffusion controlled for batch DS 1 tablets and Super Case II transport for

batches DS 2, DS 2’, DS 3, DS 4, DS 5, DS 6 and DS C. The kinetics of release were

predominantly First order for batches DS 2, DS 2’, DS 3, DS 4, DS 5, DS 6 and DS C, while

Higuchi Square root law of kinetics was for batch DS 1 tablets.

Tablets from batches DS 2’, DS 4 and DS C released approximately half their content of

diclofenac sodium in 12 hours and the rest in the next 12 hours. This made them suitable as

sustained release formulation that can be administered once daily. Tablets from batches DS 3,

DS 6 and DS 5 released not less than 70% of their diclofenac sodium content within the first 12

hours. They were not suitable as sustained release formulations and their release profile were

close to that of a conventional tablet. Tablets from batches DS 2 and DS 1 showed very poor

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release profile (less than 32%) in the first 12 hours. They may require the addition of more

channeling agents to enhance their release profile.

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CHAPTER ONE

1.0: INTRODUCTION

1.1: Sustained – Release Tablets

A sustained – release tablet is a drug product formulation that provides the required dosage

initially and then maintains or repeats it at desired intervals.

Sustained – release tablets are designed to release the drug slowly after ingestion. The main

factor in the more widespread use of these types of dosage forms is that patient compliance is

improved, since only one or two tablets need to be taken daily (1).

Reza M. S et al, reported that in the last two decades, sustained – release dosage forms have

made significant progress in terms of clinical efficacy and patient compliance. Preparation of

drug – embedded matrix tablet that involves the direct compression of a blend of drug, retardant

material and additives is one of the least complicated approaches for delivering drug in a

temporal pattern into the systemic circulation. The matrix system is commonly used for

manufacturing sustained – release dosage forms because it makes such manufacturing easy. A

wide array of polymers has been employed as drug retarding agents each of which presents a

different approach to the matrix concept. Polymers forming insoluble or skeleton matrices

constitute the first category of retarding materials, also classed as plastic matrix systems. The

second class represents hydrophobic and water – insoluble materials, which are potentially

erodible, while the third group includes polymers that form hydrophilic matrices (2).

1.1.1: Formulation of Sustained – Release Tablets

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Sustained – release tablets can consist of two parts: an immediately available dose and a

sustaining part, containing many times the therapeutic dose for protracted blood drug levels. The

immediately available dose is normally directly added to the sustaining part of the tablet or

alternatively is incorporated in the tablet coating with the sustaining portion in the core of the

tablet (1).

Uncoated sustained – released tablets are prepared by embedding the drug in the tablet matrix.

The matrix system can be of three types -

i. Plastic matrix system

ii. Hydrophobic matrix system

iii. Hydrophilic matrix system

Plastic matrix systems have been widely used for sustaining the release of drug due to their

chemical inertness and drug embedding ability. Liquid penetration into the matrix is the rate –

limiting step in such systems unless channeling agents are used.

The hydrophobic matrix systems are potentially erodible and control the release of drug through

pore diffusion and erosion (3).

The hydrophilic matrix system, when exposed to an aqueous medium does not disintegrate but

immediately after hydration develops a highly viscous gelatinous surface barrier which controls

the drug release from, and liquid penetration into the centre of the matrix system (4).

1.1.2: Methods of Achieving Sustained – Release

Sustained – release can be achieved through various methods such as:

i. Diffusion – controlled release

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ii. Dissolution – controlled release

iii. Release controlled by ion exchange

iv. Release controlled by osmotic pressure.

.1.2.1: Diffusion – Controlled Release

Diffusion involves the movement of drug molecules from region of high concentration in the

tablet to one of a lower concentration in the gastrointestinal fluids. The rate at which

diffusion occurs will depend upon the surface, the diffusional pathway, the drug

concentration gradient and the diffusion coefficient of the system. In any one dosage form

these factors will be kept constant so that a predetermined diffusion rate of drug out of the

tablet will be achieved. In practice, diffusion – controlled release can be produced by

formulating the drug in an insoluble matrix. The gastrointestinal fluids penetrate the matrix

and drug diffuses out of the matrix and is absorbed. Alternatively the drug particles can be

coated with a polymer coat of defined thickness. In this case the portion of the drug which

has dissolved in the polymer coat diffuses through an unstirred film of fluid into the

surrounding liquid. In both cases a constant concentration of drug and a constant area of

diffusion, together with a constant diffusional pathway are essential to achieve a constant

drug release (1).

With matrix tablets the initial dose is normally placed in the coat of the tablet. The coat and

the matrix can be tableted together by compression coating or the coat can be applied using a

coating pan or air suspension technique. In non – coated systems the initial dose is normally

tableted with the matrix granulation. Matrix can be composed of polymeric materials such as

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methycellulose or insoluble plastic inert substances such as methylmethacrylate (1). Higuchi

found that for matrix tablets a plot of the square root of time against amount of drug released

produced a straight line and this square root plot is often used to record the dissolution rate of

matrix tablets (5).

1.1.2.2: Dissolution – Controlled Release

Dissolution can be employed as the rate – limiting step in sustained – release tablets. Drugs

with poor dissolution rates are inherently prolonged but with water – soluble drugs it is

possible to incorporate a water – insoluble carrier into the tablet formulation to reduce

dissolution. Prolonged drug action can also be achieved by leaving out the disintegrating

agent in the tablet formulation. Encapsulation drug products also utilize dissolution to control

release. With these products, individual drug particles or granules are coated with a slowly

soluble coating material such as polyethylene glycol of varying thickness. The time required

for dissolution of the coat is proportional to the coating thickness. The coated particles can be

compressed directly into tablets. A pulsed dosing effect is obtained by tableting a small

number of different thickness coated particles or more usually by utilizing a spectrum of

different thickness coatings (1).

1.1.3: Benefits of Sustained – Release Tablets:

i. Sustained release can mean less frequent dosing for short half – life drugs and

thus better compliance.

ii. More consistent result due to reduction in variations in plasma/blood levels

iii. No need to wake patient until morning, as the drug’s activity can be extended

to take effect throughout the night.

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iv. The severity and frequency of untoward side effects are reduced with sustained

– release medications. Aspirin for example, has been shown to produce less

gastric bleeding when formulated as a sustained – release formulation than

conventional aspirin preparations (1).

1.1.4: Disadvantages of Sustained – Release Tablets

i. There may be more erratic result due to more complicated formulation.

ii. A sustained – release product may contain a larger dose, i.e. the dose for

two or three (or more) ‘normal’ dosing intervals which may be difficult

to swallow.

iii. A failure of the controlled release mechanism may result in release of a

large toxic dose.

iv. It involves more expensive technology. Therefore the cost per unit dose of

a sustained – release tablet is more than that of same unit of a conventional

tablet.

v. Accidental poisoning with sustained – release dosage forms does present

special treatment problems not seen with conventional oral tablets. The

slow release of the drug into the gastrointestinal tract and its extended

absorption often results in slow clearance of drug from the body.

1.1.5: Mechanism of drug release from wax matrices

The mechanism of drug release from wax matrices has been a matter of controversy since wax

– systems tend to be crude and more heterogeneous than other classes of polymeric systems (6).

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In some cases, it has been reported that the mechanism of release from wax matrices involves the

leaching of drug by the eluting medium. Fluid enters through the cracks and pores of the matrix

with diffusion of drug through the matrix being insignificant (7, 8). Others have reported that

release from a typical wax matrix is diffusion – controlled and is best described by Higuchi’s

Square root model (9).

1.2: Carnauba Wax

Carnauba, also called Brazil wax and palm wax is a wax of the leaves of the palm,

copernicia prunifera, a plant native to and grown in the northeastern Brazilian states of Piaui,

Ceara, Rio Grande do Norte (10). It is known as ‘’ queen of waxes’’ (11) and usually comes in

the form of hard yellow – brown flakes. It is obtained from the leaves of the carnauba or fan

palm by collecting them, beating them to loosen the wax, then refining and bleaching the wax.

1.2.1: Composition

Carnauba wax contains mainly esters of fatty acids (80 – 85%), fatty alcohols (10 – 16%), acids

(3 -6%) and hydrocarbons (1 – 3%). Specific for carnauba wax is the content of esterified fatty

diols (about 20%), hydroxylated fatty acids (about 6%) and cinnamic acid (about 10%).

Cinnamic acid, an antioxidant, may be hydroxylated or methoxylated.

1.2.2: Physicochemical properties

It has a melting point: 82 – 860C (180 – 1870F), among the highest of natural waxes.

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Its relative density is about 0.97. It is among the hardest of natural waxes, being harder than

concrete in its pure form. It is practically insoluble in water, soluble on heating in ethylacetate

and in xylene, practically insoluble in ethyl alcohol.

1.2.3: Uses

Carnauba wax can produce a glossy finish and as such is used in automobile waxes, shoe

polishes, dental floss, food products such as sweets, instrument polishes, and floor and furniture

waxes and polishes, especially when mixed with beeswax and with turpentine.

Its hypoallergenic and emollient properties as well as its shine makes it to be used in cosmetics

formulas where it is used to thicken lipstick, eyeliner, mascara, eye shadow, foundations,

deodorant and various skin care preparations.

It is used in the pharmaceutical industry as a tablet – coating agent.

1.3: Arthritis

Arthritis is a group of conditions involving damage to the joints of the body. There are over 100

different forms of arthritis (12). The most common form, osteoarthritis (degenerative joint

disease) is a result of trauma to the joint, infection of the joint, or age. Other arthritis forms are

rheumatoid arthritis, psoriatic arthritis, and autoimmune diseases in which the body attacks itself.

Septic arthritis is caused by joint infection.

Arthritis can be classified as the primary forms or secondary to other diseases. Primary forms of

arthritis include;

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i. Osteoarthritis

ii. Rheumatoid arthritis

iii. Septic arthritis

iv. Gout and pseudo – gout

v. Juvenile idiopathic arthritis

vi. Still’s disease

vii. Ankylosing spondylitis

Secondary forms may be due to diseases such as;

i. Haemochromatosis

ii. Hepatitis

iii. Lyme disease

iv. Psoriatic arthritis

v. Reactive arthritis

vi. Inflammatory bowel disease (including Crohn’s Disease and ulcerative colitis) etc.

The major complaint by individuals who have arthritis is pain. Pain is often a constant and daily

feature of the disease. The pain may be localized to the back, neck, hip, knee or feet. The pain

from arthritis occurs due to inflammation that occurs around the joint, damage to the joint from

disease, daily wear and tear of joint, muscle strains caused by forceful movements against stiff,

painful joints and fatigue.

1.3.1: Signs and Symptoms

Irrespective of the type of arthritis, the common symptoms for all arthritic disorders include

varied levels of pain, swelling, joint stiffness and sometimes a constant ache around the joint(s).

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Arthritic disorders like lupus and rheumatoid can also affect other organs in the body with a

variety of symptoms (12).

1.3.2: Treatment

There is no cure for either rheumatoid or osteoarthritis but treatments are available for a variety

of symptoms

1.3.3: Non Steroidal Anti Inflammatory Drugs (NSAIDs)

As the class name suggests, non steroidal anti-inflammatory drugs (NSAIDs) reduce

inflammation but are not related to steroids which also reduce inflammation. NSAIDs work by

reducing the production of prostaglandins. Prostaglandins are chemicals that promote

inflammation, pain and fever. They also protect the lining of the stomach and intestines from the

damaging effects of acid and promote blood clotting by activating blood platelets. Prostaglandins

also affect kidney function.

The enzymes that produce prostaglandins are called cycloxygenase (Cox). There are two types of

Cox enzymes, Cox – 1 and Cox – 2. Both enzymes produce prostaglandins that promote

inflammation, pain and fever; however, only Cox – 1 produces prostaglandins that activate

platelets and protect the stomach and intestinal lining.

NSAIDs block Cox enzymes and reduce production of prostaglandins thereby producing relief

from inflammation, pain and fever.

Other mechanisms may exist as well, such as inhibition of lipoxygenase, leukotriene synthesis,

lysosomal enzyme release, neutrophil aggregation and various cell membrane functions. They

may also suppress rheumatoid factor production.

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NSAIDs can be divided into selective and non – selective Cox – 2 inhibitors. Selective Cox – 2

inhibitors include celecoxib and nimesulide. Non – selective Cox – 2 inhibitors include;

i. The Pyrazolon derivatives such as phenylbutazone,

ii. The Methylated indole derivatives such as indomethacin,

iii. The fenamates such as mefenamic acid,

iv. The propioic acid derivates such as ibuprofen,

v. The Oxicam such as piroxicam and

vi. The phenylacetic acid derivatives such as Diclofenac.

Diclofenac is commonly used as two of its salt form namely potassium and sodium. Diclofenac

potassium has faster onset of action, therefore mainly used in acute cases while Diclofenac

sodium has slower onset of action and used mainly in chronic cases such as rheumatoid arthritis.

1.4: Diclofenac sodium

Diclofenac Sodium enteric – coated tablet is a benzene – acetic acid derivative.

Diclofenac Sodium contains not less than 99.0per cent and not more than the equivalent of 101.0

per cent of Sodium 2 – [(2, 6 – dichlorophenyl) amino] phenyl acetate, calculated with reference

to the dried substance (13).

The molecular weight is 318.14. Its molecular formula is C14H10CL2NNaO2, and it has the

following structural formula.

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Fig 1: Structure of Diclofenac Sodium

It is a white or slightly yellowish, crystalline powder, slightly hygroscopic, sparingly soluble in

water, freely soluble in methanol, soluble in alcohol, slightly soluble in acetone. It melts at about

280oC with decomposition (13).

It is one of the most useful NSAIDs agent and it is a practically insoluble compound in acidic

solution (p k = 4.0), but dissolves in intestinal fluid and water (14).

1.4.1: Therapeutic Indication, Dose and Therapeutic Index

Diclofenac is used for long – term symptomatic treatment of rheumatoid arthritis, osteoarthritis

and ankylosing spondylitis (15).

It may also be useful for short – term treatment of acute musculoskeletal injury, acute painful

shoulder (bicipital tendinitis and subdeltoid bursitis), postoperative pain, and dysmenorrheal

(15).

Rheumatoid arthritis and osteoarthritis are chronic diseases and their management requires use of

drug for a long period of time. The usual dose of Diclofenac Sodium in osteoarthritis is 50mg 2

to3 times daily or 75mg twice daily. In rheumatoid arthritis, the dose is 50mg 3 to 4 times daily

or 75mg twice daily. For analgesia and primary dysmenorrheal, the recommended starting dose

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is 50mg, 3 times daily. Compliance is usually a problem. Controlled – release Diclofenac

Sodium 100mg tablet is given once daily. This improves compliance and ultimately therapeutic

success.

1.4.2: Pharmacokinetic Properties of Diclofenac Sodium

1.4.2.1: Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as

measured by urine recovery. However, due to first – pass metabolism, only about 50% 0f the

absorbed dose is systemically available. Food has no significant effect on the extent of

Diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5

hours and a reduction in peak plasma levels of

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1.4.2.3: Metabolism

Five Diclofenac metabolites have been identified in human plasma and urine. The metabolites

include 4’ – hydroxyl - , 5 – hydroxyl -, 3’ – hydroxyl -, 4’, 5 – dihydroxy – and 3’ – hydroxyl –

4’ – methoxy Diclofenac. In patients with renal dysfunction, peak concentrations of metabolites

4’ – hydroxyl – and 5 – hydroxyl – Diclofenac were approximately 50% and 4% of the parent

compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

However, Diclofenac metabolites undergo further glucuronidation and sulfation followed by

biliary excretion.

One Diclofenac metabolite 4’ – hydroxyl – Diclofenac has very weak pharmacologic activity

(16).

1.4.2.4: Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the

glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged Diclofenac

is excreted in the urine. Approximately 65% of the dose is excreted in the urine and

approximately 35% in the bile as conjugates of unchanged Diclofenac plus metabolites. Because

renal elimination is not a significant pathway of elimination for unchanged Diclofenac, dosing

adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal

half – life of unchanged Diclofenac is approximately 2 hours (16).

1.5: Melt Granulation

Melt granulation could be an easy and fast method to formulate sustained release tablets (17).

Melt granulation is a well known process whereby fine powders are agglomerated by means of a

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molten binder and processed into spherical or nearly spherical granules of homogeneous size.

With hydrophobic binders and appropriate fillers sustained – release systems can be obtained by

this process (18).

Melt granulation of the matrix granules is achieved by mixing a drug powder/or granule with a

melt of a wax material (e.g. Carnauba wax or glyceryl monostearate), with the objective of

coating the granules and further retarding drug release from the granules. Thus, matrix

granulation and wax coating of the matrix granules are approaches for retarding drug release and

hence prolonging the biologic action of drugs with short biologic half life (19).

Melt granulation is one of the most widely applied processing techniques in the array of

pharmaceutical manufacturing operations. Melt granulation process is currently applied in the

pharmaceutical for the manufacture of variety of dosage forms and formulation such as

immediate release and sustained – release pellets, granules and tablets (20).

1.5.1: Uses

Melt granulation is used to;

i. Improve the dissolution rate and bioavailability of the drug by forming a solid

dispersion or solid solution.

ii. Control or modify the release of the drug.

iii. Mask the bitter taste of an active drug.

1.5.2: Advantages

i. Neither solvent nor water is used in the process.

ii. Fewer processing steps needed thus time consuming drying steps eliminated.

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iv. There are no requirements on the compressibility of active ingredients and the entire

procedure is simple, continuous and efficient.

v. Uniform dispersion of fine particles occurs.

vi. Good stability at varying pH and moisture levels.

vii. Safe application in humans due to their non – swellable and water insoluble nature.

1.5.3: Disadvantages

i. Requires high energy input.

ii. It cannot be applied to heat – sensitive materials owing to the elevated

temperatures.

iv. Lower – melting point binder risks situation where melting or softening of the binder

occurs during handling and storage of the agglomerates.

1.5.4: Dissolution Test

Whilst the test for tablet disintegration gives some control over those drugs whose bioavailability

from tablets is governed by the rate at which the tablet disintegrates, it gives no information

regarding those cases where the tablet disintegrates satisfactorily, but the rate – limiting step is

the rate at which the active drug substance dissolves in the fluids of the gastrointestinal tract

(21).

Dissolution test is a measure of the proportion of drug dissolving in a stated time under

standardized conditions in vitro (21).

The principal purposes of dissolution testing are 3 – fold:

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1. For quality control, to ensure the uniformity of product from batch to batch.

2. To help to predict bioavailability for formulation development.

3. As a measure of change when formulation changes are made to an existing formulation

(22).

Bai et al also supported the above points in their work;

They wrote that in the pharmaceutical industry, drug dissolution testing is routinely used to

provide critical in vitro drug release information for both quality control purposes, i.e., to assess

batch to batch consistency of solid oral dosage forms such as tablets, and drug development, i.e.,

to predict in vivo drug release profiles (a).

In vitro drug dissolution data generated from dissolution testing experiments can be related to in

vivo pharmacokinetic data by means of in vitro-in vivo correlations (IVIVC). A well established

predictive IVIVC model can be very helpful for drug formulation design and post-approval

manufacturing changes (b).

The main objective of developing and evaluating an IVIVC is to establish the dissolution test as

a surrogate for human bioequivalence studies, as stated by the Food and Drug Administration

(FDA). Analytical data from drug dissolution testing are sufficient in many cases to establish

safety and efficacy of a drug product without in vivo tests, following minor formulation and

manufacturing changes (Qureshi and Shabnam, 2001). Thus, the dissolution testing which is

conducted in dissolution apparatus must be able to provide accurate and reproducible results.

Several dissolution apparatuses exist. In United States Pharmacopeia (USP), there are four

dissolution apparatuses standardized and specified (c). They are:

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• USP Dissolution Apparatus 1 - Basket (37°C)

• USP Dissolution Apparatus 2 - Paddle (37°C)

• USP Dissolution Apparatus 3 - Reciprocating Cylinder (37°C)

• USP Dissolution Apparatus 4 - Flow-Through Cell (37°C)

The performances of dissolution apparatuses are highly dependent on hydrodynamics due to the

nature of dissolution testing. The designs of the dissolution apparatuses and the ways of

operating dissolution apparatuses have huge impacts on the hydrodynamics, thus the

performance

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CHAPTER TWO

2.0: MATERIALS AND METHODS

I: Materials

Diclofenac Sodium (Alpha Lab, Germany), Carnauba wax, refined NO 1, yellow (Sigma –

Aldrich U.K), Hydrochloric acid 37% (Haig Laboratory Chemical Corporation Wembley,

MIDDX, England), Potassium dihydrogen orthophosphate (BDH Chemicals Ltd Poole England).

Potassium Hydroxide (BDH Chemicals Ltd Poole England), Microcrystalline cellulose (N.B

Entrepreneur Nagpur India), Magnesium stearate and Silicon dioxide.

II: Methods

2.1.1: Preformulation studies

Development of calibration curve for Diclofenac Sodium:

A stock solution of Diclofenac sodium was prepared by dissolving 100mg of drug in 100ml of phosphate

buffer of pH 6.8 (0.1%w/v) . From this stock solution, 0.06%, 0.04%, 0.006%, 0.004%, 0.003%, 0.002%,

0.0006%, 0.0004%, 0.0003%, 0.0002%, 0.00006%, 0.00004%, 0.00002%, 0.000004%, 0.000002% w/v

dilutions were prepared. The �max of the drug was determined by scanning one of the dilutions between

400 to 200 nm using a UV- visible spectrophotometer.

2.1.2: Preparation of Formulations DS 1 – DS 6 of Diclofenac Sodium Granules

Diclofenac sodium was prepared by melt granulation using the quantities of active ingredients

and excipients as in table 2 below.

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Diclofenac sodium was blended thoroughly with microcrystalline cellulose in a polyethylene

bag. Carnauba wax was placed in a beaker and heated to about 880C using a water – bath.

The mixture of Diclofenac sodium and diluents was added to the melted carnauba wax and

blended together. It was allowed to cool. The granules formed were passed through sieve NO

100. This was formulation DS 1.

Formulations DS2, DS2’, DS3, DS4, DS5 and DS6 of Diclofenac sodium granules were

prepared as in DS1 but using the quantities of excipients as in table 2 below.

Table 1: Formulations for Preparing Batches DS1 – DS6 of Diclofenac Sodium Granules

DS1

DS2

DS2’

DS3

DS4

DS5

DS6

Diclofenac

sodium

100mg

100mg

100mg

100mg

100mg

100mg

100mg

Carnauba

wax

300mg

200mg

200mg

100mg

175mg

150mg

125mg

MCC

0mg

100mg

100mg

200mg

125mg

150mg

175mg

Magnesium

2mg

2mg

2mg

2mg

2mg

2mg

2mg

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stearate

Cab - O –

Sil

4mg

4mg

4mg

4mg

4mg

4mg

4mg

TOTAL

406mg

406mg

406mg

406mg

406mg

406mg

406mg

Table 2: Formulations for preparing 200 tablets of the respective Batches DS 1 – DS 6 of

Diclofenac Sodium Granules

DS 1 DS 2 DS 2’ DS 3 DS 4 DS 5 DS 6

Diclofenac

Sodium

20g 20g 20g 20g 20g 20g 20g

Carnauba Wax

60g 40g 40g 20g 35g 30g 25g

Microcrystalline

Cellulose

0g 20g 20g 40g 25g 30g 35g

Magnesium

Stearate

0.4g 0.4g 0.4g 0.4g 0.4g 0.4g 0.4g

Silicon dioxide 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g 0.8g

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Total

81.2g 81.2g 81.2g 81.2g 81.2g 81.2g 81.2g

2.1.3: Compression of Batches DS 1 – DS 6 of Diclofenac Sodium Granules

0.4g of magnesium stearate and 0.8g of silicon dioxide were mixed thoroughly with respective

quantities of Diclofenac sodium granules formulation DS1 – DS6. A 406mg sample of the

blended Diclofenac sodium granules was used to calibrate the die volume of the Manesty F3

single Punch Tableting Machine (Liverpool, England) using an 8mm punch. The tableting

machine was operated manually. The granules from batches DS1, DS2 and DS3 were then

compressed into tablets respectively using the aforementioned tablet press at a predetermined

compression pressure (21). The granules from batches DS2’, DS4, DS5 and DS6 were then

compressed into tablets respectively using a Cadmach SSF3 single punch tableting machine

(Ahmedabad, India) with 12.5mm punch at a predetermined compression pressure.

2.2: Dissolution Test Studies for Formulations DS1 – DS6 and DSC (Voltaren Retard)

Tablets

In – vitro dissolution test study was done using a - six station USP type 1 apparatus (DBK

Dissolution test equipment) for 12 hours at 37±1.00C and speed of 50rpm.

One tablet each from DS1 (407mg), DS2 (405.5mg), DS3 (405.7mg) and DSC (302.9mg) was

placed in the basket of the respective stations of the Dissolution test equipment. The initial 2

hours was done in simulated gastric acid medium (0.1N HCl) and the rest 10 hours in a

phosphate buffer at pH 6.8 under sink condition. 10ml of samples were withdrawn from the

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dissolution medium and replaced with 10ml of fresh medium to maintain constant volume every

1 hour. After filtration, the sample solution was analyzed at 270nm for Diclofenac sodium using

a DBK UV spectrophotometer. Twelve samples were collected at respective 12 hours for each of

formulations DS1, DS2, DS3 and DSC. This was repeated in triplicate. The above process was

repeated in triplicate for batches DS2’ (406mg), DS4 (407mg), DS5 (406.5mg), DS6 (405.8mg)

and DSC (303mg).

2.3: Friability Test

DBK Friability Test Apparatus made by DBK Mumbai instruments was used. 10 tablets from

batch DS1 were weighed (4058mg) and placed at the right hand side (RHS) of the apparatus

while another 10 tablets were weighed (3980mg) and placed at the left hand side (LHS). The

apparatus was set to make 100 revolutions after which the tablets were re – weighed.

This was repeated for batches DS2 (RHS = 4004mg, LHS = 4108mg), DS2’ (RHS = 4110mg, LHS =

4090mg), DS3 (RHS = 4041mg, LHS = 4049mg), DS4 (RHS = 4080mg, LHS = 4100mg), DS5 (RHS =

4060mg, LHS = 4040mg) and DS6 (RHS = 4090mg, LHS = 4085mg).

2.4: Uniformity of Weight Test

About 20 tablets from formulations DS1 were weighed and the mean weight determined. This

was repeated for formulation DS2, DS2’, DS3, DS4, DS5 and DS6. The mean weight governs

the permitted deviations from the mean. These are given in table 3 below.

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Table 3: Uniformity of tablet weight (22)

Average weight of tablet Percentage deviation

80mg or less 10

More than 80mg and less than 250mg 7.5

250mg or more 5

2.5: Determination of Crushing Strength of Batches DS 1 - DS 6 of Diclofenac Sodium

Tablets.

The crushing strengths of the tablets were determined with Shital Scientific tablet hardness tester

using ten tablets immediately after compression.

2.6: Melting Point Determination

Capillary tube was filled with small quantity of the Diclofenac sodium powder and placed in a

DBK Melting Point apparatus. The melting point was determined. The melting point for

carnauba wax was also determined.

2.7: Preparation of Buffer Solutions

2.7.1: Preparation of Buffer Solution of pH 12

A 2g sample of NaCl was dissolved in about 950ml of distilled water. The p H of the solution

was adjusted to 1.2 using concentrated HCl and the volume of the solution made up to 1000ml

with distilled water.

2.7.2: Preparation of Phosphate Buffer Solution of pH 6.8

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A 0.5g sample of Potassium Dihydrogen Phosphate (NaH2PO4) was dissolved in about 950ml of

distilled water and the pH of the solution adjusted to 6.8 with 0.4N NaOH. The volume of the

solution was made up to 1000ml with distilled water.

2.8: Analysis of Data

Statistical analysis was done using Microsoft Excel and SPSS version 17.0. Data were analyzed by one –

way ANOVA. Differences between means were assessed by a two – tailed student’s T – test. P < 0.05

was considered statistically significant.

The dissolution kinetics of Diclofenac sodium from formulations DS1, DS2, DS2’, DS3, DS4,

DS5, DS6 and DSC tablets in phosphate buffer solution of p H 6.8 were determined by

application of the Zero Order, First Order, Higuchi and Hixson – Crowell’s Cuberoot Law . The

mechanism of drug release was obtained by fitting the first 60% drug release data into the

Korsmeyer – Peppas model as shown below:

Zero Order Model

C = K…………………………………………………………………………… (23, 24, 25)

C = %Release, K0 = Zero Order rate constant expressed in units of concentration/time (t).

First Order Model

LogCr = LogC0 – K1t/2.303…………………………………………………………… (23, 24, 25)

Cr = %Remaining, C0 = Initial concentration of drug, K1 = First Order constant, t = Time

Higuchi’s Square root Law Model

Q = KHt1/2……………………………………………………………………………… (5, 25, 26)

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Q = %Released, KH = Constant reflecting design variables of the system, t = Time

Hixson – Crowell’s Cuberoot Law Model

[(100 – f)/100]1/3 = 1 – KHCt………………………………………………………………… (27)

f = %Released, KHC = Rate constant, t = Time

Korsmeyer – Peppas Model

Mt/M� = Ktn……………………………………………………………………………… (28, 29)

Mt/M� = Fraction of drug released at time (t), K = Rate constant, ‘n – value’ is used to

characterize different release mechanisms.

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CHAPTER THREE

3.0: RESULTS AND DISCUSSION

3.1: Evaluation of Diclofenac Sodium

3.1.1: Pre formulation studies

Calibration curve for Diclofenac sodium was developed by scanning the drug solution in the UV range

and it showed maximum absorbance at 270 nm. The calibration curve was developed at this wavelength.

The values are given in Table 4 below

Table 4: Calibration curve table for Diclofenac sodium

CONCENTRATION(g/%ml) ABSORBANCE(nm)

0.000000 0.000

0.000318 0.179

0.000636 0.281

0.000954 0.462

0.001230 0.522

0.001590 0.630

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Fig 2: Calibration curve plot for diclofenac sodium.

3.1.2: Melting point of Diclofenac Sodium

Diclofenac sodium melted at 2800C with decomposition.

3.1.3: Melting point of Carnauba Wax

It melted between 820C and 860C.

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3.1.4: Crushing Strengths of Batches 1 – 6 Diclofenac Sodium Tablets

The crushing strength of Batches 1 – 6 diclofenac sodium tablets are shown in Table 5 below.

Table 5: Crushing Strengths of Batches 1 – 6 Diclofenac sodium Tablets

BATCH HARDNESS(kgf)

DS 1 7.5

DS 2 7.7

DS 2’ 7.0

DS 3 7.6

DS 4 7.9

DS 5 7.8

DS 6 7.0

3.1.5: Tablets Dimensions

The tablet diameter for batches DS1, DS2 and DS3 tablets was 10mm and the thickness was

5mm (a single station F3 Manesty tableting machine with 8mm punch was used). The tablet

diameter for batches DS2’, DS4, DS5 and DS6 tablets was 13mm and the thickness was 3mm (a

single station SSF3 Cadmach tableting machine with 12.5mm punch was used).

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Fig. 3: The Sequential release of Diclofenac Sodium from batches DS1 (100mg diclofenac

sodium, 300mg carnauba wax), DS2 (100mg diclofenac sodium, 200mg carnauba wax),

DS2’ (100mg diclofenac sodium, 200mg carnauba wax), DS3 (100mg diclofenac sodium,

100mg carnauba wax), DS4 (100mg diclofenac sodium, 175 carnauba wax), DS5 (100mg

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diclofenac sodium, 150mg carnauba wax), DS6 (100mg diclofenac sodium, 125 carnauba

wax)and DSC (Voltaren retard 100mg) Tablets.

3.2.1: In Vitro Drug Release Characteristics of Formulation DS1 of Diclofenac Sodium

Tablets:

The in vitro drug release characteristics of diclofenac sodium from formulation DS1 tablets are

shown in fig. 4 – 9.

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Fig. 4: Sequential Release of Diclofenac Sodium from batch DS1 (100mg diclofenac sodium,

300mg carnauba wax) Tablets in Aqueous Media of pH 1.2 (2 hours) and phosphate buffer,

pH 6.8 (10 hours).

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The mean (± s.d.) percent of in vitro drug release of Diclofenac sodium from batch DS1 tablets

as in fig. 4 above showed that only 6.44 ±0.05% of Diclofenac sodium was released after the first

2 hours in the simulated gastric fluid of pH 1.2. This showed the poor solubility of the

Diclofenac sodium at the acidic pH of 1.2.

The plot in fig. 4 above showed approximately a straight line, indicating controlled release.

However, a cumulative quantity of 23.86 ± 0.06% was released after 12 hours (2hours at p. H.

1.2 and 10 hours in the simulated intestinal fluid of pH 6.8), which showed a poor release profile

for the batch. This may be due to the high concentration of the hydrophobic matrix (75% of

carnauba wax) in the batch.

When the dissolution result was fitted into several kinetic models as shown in fig. 5 – 9 below, it

was obvious that Higuchi’s Square root Law, First Order, Cuberoot Law and Zero Order Kinetics

were all in operation during drug release. But Higuchi’s Square root Law Kinetic was most

dominant, which shows that drug release from the tablet matrix was diffusion dependent with

average diffusion rate of 7.60% per hr1/2. The mechanism of drug release was determined by the

application of the Korsmeyer – Peppas equation which gave an n – value of 0.858 and this is

indicative of an anomalous (non – fickian) diffusion controlled mechanism of release (23, 24,

25). This means that the release profile does not obey Fick’s Law of Diffusion (30).

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Fig. 5: Zero Order Release Plot of Diclofenac Sodium from batch DS1 (100mg diclofenac

sodium, 300mg carnauba wax) Tablets.

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Fig. 6: First Order Plot of Release Diclofenac Sodium from batch DS1 (100mg diclofenac


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Fig. 7: Higuchian Plot of the release of Diclofenac Sodium from batch DS1 (100mg

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Fig. 8: Korsmeyer – Peppas Plot of the Release of Diclofenac Sodium from batch DS1

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Fig. 9: Cuberoot Plot of the Release of Diclofenac Sodium from batch DS1 (100mg


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3.2.2: In Vitro Drug Release Characteristics of Diclofenac Sodium from batch DS2 Tablets:

The in vitro drug release characteristics of Diclofenac Sodium from batch DS2 tablets are shown

in fig. 10 – 15.

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Fig. 10: Sequential Release of Diclofenac Sodium from batch DS2 (100mg diclofenac


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From fig. 10 above, it showed that the plot was almost a straight line indicating a controlled

release process. The drug release profile of 3.88 ± 0.03% within the first 2 hours showed good

drug release retardation by the matrix system at acidic pH.

The drug release of 13.25 ± 0.05% and 31.08 ± 0.10% after 1 hour and 10 hours respectively in

simulated intestinal fluid showed appreciable release when compared to batch DS1.

When the dissolution results were fitted into different release kinetic models as shown in fig.11 –

15, it was observed that Zero Order Kinetics, First Order Kinetics, Higuchi’s Square root Law

and Cuberoot Law were all in operation but First Order Kinetics was the most dominant. The

mechanism of drug release was determined by application of the Korsmeyer – Peppas equation

which gave an n – value of 0.953 and this is indicative of super case - II transport.

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Fig. 11: Zero Order Plot of the Release of Diclofenac Sodium from batch DS2 (100mg

diclofenac sodium, 200mg carnauba wax) Tablets

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(100mg diclofenac sodium, 200mg carnauba wax) Tablets

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3.2.3: In Vitro Drug Release Characteristics of Diclofenac Sodium from batch DS2’

Tablets:

The in vitro drug release characteristics of Diclofenac sodium from batch DS2’ tablets are shown

in fig. 16 – 21.

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Fig. 16: Sequential Release of Diclofenac Sodium from batch DS2’ (100mg diclofenac

sodium, 200mg carnauba wax) Tablets

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Fig. 18: First Order Plot of the Release of Diclofenac Sodium from batch DS2’ (100mg


��4($(") �9�"$(%-

&'��($)*-

(

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Fig. 19: Higuchian Plot of the Release of Diclofenac Sodium from Batch DS2’ (100mg


��%+$"*

&'��($*)+

(

%(

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Fig. 20: Korsmeyer – Peppas Plot of the Release of Diclofenac Sodium from batch DS2’

(100mg diclofenac sodium, 200mg carnauba wax) Tablets

��%$*(! �9�($(!#

&'��($-**

(

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Fig. 21: Cuberoot Plot of the Release of Diclofenac Sodium from Batch DS2’ (100mg


��4($("( �9�%$(%+

&'��($)*(

(

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($-

%

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3.2.4: In Vitro Drug Release Characteristics of Diclofenac Sodium from Formulation DS3

Tablets:

The in vitro drug release characteristics of Diclofenac sodium from batch DS3 tablets are shown

in fig. 22 – 27.

4"(

(

"(

!(

,(

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Fig. 22: Sequential Release of Diclofenac Sodium from batch DS3 (100mg diclofenac


From fig. 22 above, it showed that only 5.76 ±0.05% of Diclofenac Sodium was released from

batch DS3 tablets after 2 hours in the simulated gastric fluid. The drug release retardation effect

of the matrix system may be as a result of poor solubility of the drug at acidic pH. A total of

47.77 ± 0.07%, 88.48 ± 0.55% and 95.94 ± 0.31% of Diclofenac Sodium were released after 1

hour, 5 hours and 10 hours respectively in simulated intestinal fluid (phosphate buffer pH. 6.8)

from formulation DS3 tablets. This showed that about 88.48 ± 0.55% and 95.0.31% of drug were

released after a total of 7 hours and 12 hours respectively and that the drug release retardation

effect of the matrix system (25% carnauba wax) in batch DS3 was weak.

When the dissolution results were fitted into different release kinetic models as shown in fig. 23

– 27 below, it appeared that all the kinetic models, Zero Order, First Order, Higuchi’s Square

root Law and Hixson – Crowell’s Cube root Law were in operation but the First Order Kinetics

Model appeared the most dominant. The mechanism of drug release was determined by the

application of Korsmeyer – Peppas equation; which gave an n – value of 1.280 indicating that

the drug release is by Super Case – II transport.

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Fig. 23: Zero Order Plot of Diclofenac Sodium from batch DS3 (100mg diclofenac sodium,

100mg carnauba wax) Tablets.

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&'��($*-,

(

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-(

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Fig. 24: First Order Plot of Diclofenac Sodium from batch DS3 (100mg diclofenac sodium,

100mg carnauba wax) Tablets.

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&'��($)*,

(

($#

%

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Fig. 25: Higuchian Plot of the Release of Diclofenac Sodium from batch DS3 (100mg


��")$,)

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3.2.5: In Vitro Drug Release Characteristics of Diclofenac Sodium from Formulation DS4

Tablets:

The in vitro drug release characteristics of Diclofenac sodium from formulations DS4 tablets are

shown in fig. 28 – 33.

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Fig.28: Sequential Release of Diclofenac Sodium from Batch DS4 (100mg diclofenac





4%(

(

%(

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Fig. 29: Zero Order Plot of the Release of Diclofenac Sodium from Batch DS4 (100mg


��4($(+% �9�"$(%*

&'��($)-"

(

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Fig. 30: First Order Plot of the Release of Diclofenac Sodium from batch DS4 (100mg


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Fig. 31: Higuchian Plot of the Release of Diclofenac Sodium from Batch DS4 (100mg


��%!$"!

&'��($-(*

(

%(

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Fig. 46: Sequential Plot of the Release of Diclofenac Sodium from Batch DSC (Voltaren

Retard) Tablets.

From fig. 22 above, it showed that 4.79 ± 2.63% of Diclofenac sodium was released within the

first 2 hours from the batch DSC tablets. 62.28 ± 2.08% of the drug was released after 12 hours

of the dissolution test study (2 hours at pH 1.2 and 10 hours at pH 6.8) which showed that the

4"(

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batch DSC can be adequately administered once daily. The release profile was almost linear

showing a regular controlled drug release.

When the dissolution result was fitted into several release kinetic models as shown in fig. 23 – 27

below, it was obvious that Zero Order , First Order, Higuchi’s Square root Law and Hixson –

Crowell’s Cube root Law were all in operation but First Order appeared to be the most dominant.

This showed that the drug release from the tablet matrix was concentration dependent. The


which gave an n – value of 1.183 and this is indicative of a Super Case II transport.

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Fig. 47: Zero Order Plot of the Release of Diclofenac Sodium from Batch DSC (Voltaren

RetardR) Tablets.

��#$-*,

&'��($)++

(

%(

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Fig. 48: First Order Plot of the Release of Diclofenac Sodium from batch DSC (Voltaren

RetardR) Tablets.

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(

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%

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!$�#!��"��#��

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Fig. 49: Higuchian Plot of the Release of Diclofenac Sodium from Batch DSC (Voltaren

RetardR) Tablets.

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Fig. 50: Korsmeyer – Peppas Plot of the Release of Diclofenac Sodium from Batch DSC

(Voltaren RetardR) Tablets.

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Fig. 51: Cuberoot Plot of the Release of Diclofenac Sodium from Batch DSC (Voltaren

RetardR) Tablets.

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Table 6: Summary of Pharmacokinetic Profiles of the Release of Diclofenac Sodium from

Batches DS1, DS2, DS2’, DS3, DS4, DS5, DS6 and DSC of Diclofenac Sodium Tablets

Kinetic Model DS1 DS2 DS2’ DS3 DS4 DS5 DS6 DSC

Zero Order

Law

K0

R2

2.560

0.601

3.034

0.897

4.688

0.959

10.19

0.786

5.015

0.956

6.748

0.921

7.352

0.799

5.876

0.933

First Order

Law

K1

R2

-0.009

0.809

-0.014

0.943

-0.029

0.978

-0.132

0.976

-0.031

0.982

-0.049

0.971

-0.049

0.932

-0.037

0.977

Higuchi’s

Square Root

Law

KH

R2

7.596

0.858

8.779

0.885

13.27

0.793

29.69

0.805

14.24

0.807

19.27

0.806

21.4

0.818

16.84

0.844

Hixson –

Crowell’s

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evaluation of carnauba wax in sustained release … eziuzo.pdf · carnauba, also called brazilwax...

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