vikesh kumar

8/13/2019 Vikesh Kumar

1/361

FFOORRMMUULLAATTIIOONN AANNDD EEVVAALLUUAATTIIOONN OOFF SSOOLLIIDD

OORRAALL DDOOSSAAGGEE FFOORRMM ((TTAABBLLEETTSS)) OOFF

SSEELLEECCTTEEDD AANNTTII--TTUUBBEERRCCUULLAARR AAGGEENNTTSS..

By

Mr. VIKESH KUMAR SHUKLA M.PHARM.

Thesis

Submitted to KLE University BelgaumKarnataka in partial fulfillment of therequirements for the degree of

Doctor of PhilosophyinPharmacy


2/361

KKLLEE UUNNIIVVEERRSSIITTYY

BBEELLGGAAUUMM--559900001100,, KKAARRNNAATTAAKKAA,, IINNDDIIAA

[Established under Section 3 of the UGC Act,1956 vide Governmentof India Notification No. F.9-19/2000-U3 (A)]

Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss tthheessiiss eennttiittlleedd FFOORRMMUULLAATTIIOONN

AANNDD EEVVAALLUUAATTIIOONN OOFF SSOOLLIIDD OORRAALL DDOOSSAAGGEE FFOORRMM

((TTAABBLLEETTSS)) OOFF SSEELLEECCTTEEDD AANNTTII--TTUUBBRREERRCCUULLAARR AAGGEENNTTSS iiss aa

bboonnaaffiiddeeaannddggeennuuiinneerreesseeaarrcchhwwoorrkkccaarrrriieeddoouuttbbyymmeeuunnddeerrtthhee


3/361



[Established under Section 3 of the UGC Act,1956 vide Government of India

Notification No. F.9-19/2000-U3(A)]

Certificate by the Guide

II hheerreebbyy ddeeccllaarree tthhaatt tthhiiss tthheessiiss eennttiittlleedd FFOORRMMUULLAATTIIOONN



bboonnaaffiiddeerreesseeaarrcchhwwoorrkkddoonneebbyyMMrr..VVIIKKEESSHHKKUUMMAARRSSHHUUKKLLAA,,iinn

ppaarrttiiaallffuullffiillllmmeennttoofftthheerreeqquuiirreemmeennttffoorrtthheeDDeeggrreeeeooffDDOOCCTTOORR

OOFF PPHHIILLOOSSOOPPHHYY IINN PPHHAARRMMAACCYY ((PPHHAARRMMAACCEEUUTTIICCSS))


4/361





ENDORSEMENT BY THE PRINCIPAL/ HEAD OF

THE INSTITUTION

II hheerreebbyyddeeccllaarree tthhaatt tthhiiss tthheessiiss eennttiittlleedd FFOORRMMUULLAATTIIOONN



bboonnaaffiiddeerreesseeaarrcchhwwoorrkkddoonneebbyyMMrr.. VVIIKKEESSHHKKUUMMAARRSSHHUUKKLLAA,,


5/361





Copyright

Declaration by the Candidate

II hheerreebbyy ddeeccllaarree tthhaatt tthhee KKLLEE UUNNIIVVEERRSSIITTYY,,

NNEEHHRRUU NNAAGGAARR,, BBEELLGGAAUUMM,, KKAARRNNAATTAAKKAA sshhaallll

hhaavvee tthhee rriigghhttss ttoo pprreesseerrvvee,, uussee aanndd ddiisssseemmiinnaattee tthhiiss

ddiisssseerrttaattiioonn iinn pprriinntt oorr eelleeccttrroonniicc ffoorrmmaatt ffoorr aaccaaddeemmiicc //

rreesseeaarrcchhppuurrppoossee..


6/361

ffe c t i o na te l y d ed ic a t e d t o m yP a r en t s a n d n s h


7/361


8/361

Acknowledgements

The completion of this dissertation is not only fulfillment of my dreams but also the dreams of

myParents, Grand parents, Big Band my sweet sisterwho have taken lots of pain for me in

completion of my higher studies.

I take this privilege and pleasure to acknowledge the contributions of many individuals who

have been inspirational and supportive throughout my work undertaken and endowed me with themost precious knowledge to see success in my endeavor. My work bears the imprint of all those people

I am grateful to.

With grate pleasure and profound sense of gratitude, I express my most cordial and humble

thanks to my eminent, respected teacher and guide Prof. (Dr.) F. V. Manvi, Principal

Department of Pharmaceutics, K.L.E. University's College of Pharmacy, Belgaum and Co-ordinator

KLE University, Belgaum for his valuable guidance, keen interest, inspiration, unflinching

encouragement and moral support throughout my dissertation work. His strict discipline, urge for

hard work, principle, simplicity and provision of fearless work environment will cherish me in all

walks of life. I am immensely thankful to Prof. A. D. Taranalli,Vice-Principal and Head,

Department of Pharmacology, K.L.E. University's College of Pharmacy, Belgaum, for providingnecessary facilities and help in carrying out this work.

It is my privilege and honor to extend my gratitude to Dr A R Bhat Professor &


9/361

Bolmal, Dr. Kunnur, Dr. ChandrashekharAsst. Professor, K.L.E. University's College

of Pharmacy, Belgaum, for their guidance and help in instrumental analysis.

I also owe my sincere thanks to senior research scholars Dr. C. R. Patil, Dr.

Thippeswamy, Dr. M. N. Noolvi, Dr. Bongade, Talat mam, Palkar Sirfor their

valuable suggestions, ever willing help and moral support during my dissertation work.

I wish to express my thanks to Prof. K. G. Bhat, Department of Microbiology, M.M.

Dental College and Research Centre, Belgaum, for actively engaging in microbiological screening of myformulations.

I very special thanks to my best friendKalpana, NIPERfor her valuable suggestions, ever

willing help and moral support during my research work.

I also wish to express my thanks toManager- R&D Centre, Macloads Pharma.

Pvt. Ltd., Mumbaifor providing me necessary facility and pure INH and Rifampicin samples for

my research work.

I express my sincere thanks to all teaching and non-teaching staff members, especiallyShri.

Deepshetty Lab. Technician, Department of Pharmsceutics, Shri. P. V. Kardi Lab.

Technician, Department of Pharmacognosy and Phytochemistry, Shri M. C. HirremathLab.

Technician, Department of Pharma. Chemistry and Store-In charge,Shri Kuri, Shri Prakash,

Shri Baganna, Shri Bijay andShri Mudgappa, K.L.E.S's College of Pharmacy, Belgaum,


10/361

Tanaji, Anand and All friends of Parampitta Hostel for their suggestions and

encouragement.

I often wonder, if one gets to see God in the moral life they might be like Parents who

showers their best fortunes always on me. From the deepest depth of my heart to express my thanks,

I bow my head to the feet of my beloved parents whose uncompromising life principles, love, affection,

has been always unshared and showered upon me at all stages of life and giving me more than what I

deserved in my life.

Last but not the least, I thank my internal belief Godwho always flowers his blessing on

me.

Thanks to one and all

Date: SHUKLAPlace: BBeellggaauumm..


11/361

CONTENTS

S. No. Particulars Page No.

1. INTRODUCTION 1 17

2. NEED AND OBJECTIVES 18 21

3. REVIEW OF LITERATURE 22 46

4. MATERIALS AND METHODS 47 72

5. RESULTS AND DISCUSSION 73 211

6. SUMMARY 212 - 215

7. CONCLUSION 216 218

8. BIBLIOGRAPHY 219 234

9. ANNEXURE 235 237


12/361

LIST OF PLATES

PLATE

NO.TITLE

PAGE

NO.

1. Fast disintegrating Tablets of Isoniazid 93

2. Disintegration of Tablet in 60 sec 93

3. Anti-Tubercular Activity-Formulations 94

4. In-vivo Bioavailability study 95

5. Scanning Electron Microscopy of Formulation F1 96









13/361

LIST OF FTIR SAMPLES

FIG.

NO.TITLE

PAGE

NO.

1. Pure Isoniazid. 108

2. Pure Rifampicin. 109

3. Pure Avisol pH102 110

4. Pure Ac-Di-Sol 111

5. Pure Poly Plastadone XL 112

6. Pure Sodiun Starch Glycolate 113

7. Pure Kollidon CL 114

8.FTIR study of Formulation F1 115







14/361

LIST OF X-RAY POWDER DIFFRACTION SAMPLES

FIG.

NO.TITLE

PAGE

NO.

1. Pure Isoniazid. 127

2. Pure Rifampicin. 128

3. Pure Avisol pH102. 129

4. Pure Ac-Di-Sol. 130

5. Pure Poly Plastadone Xl. 131

6. Pure Sodiun Starch Glycolate(SSG). 132

7. Pure Kollidon Cl 133

8.X-ray Powder study of Formulation F1 134





13


15/361

LIST OF TABLES

TABLE

NO.TITLE

PAGE

NO.

1. Composition of fast-disintegrating formulations 146

2.

Standard Calibration Curve of Isoniazid and Rifampicin at 261 nm and

333nm in PB 6.8 147

3.Pre-compression parameters of formulations: Angle of Repose, Loose

Bulk Density, Tapped Bulk Density, Carr's Compressibility Index148

4.Post compression tablet Parameters: Uniformity of thickness, Hardness,

Weight, Drug content uniformity, Friability, Test of dispersion.149

5.Post compression tablet Parameters: Wetting Time, Water Absorption

Ratio150

6.Post compression tablet Parameters:In vitroDisintegration Time,In

vivoDisintegration Time, Mouth Feel151

7. In vitro Dissolution Profile of the pure Isoniazid 152

8. In vitro Dissolution Profile of the Isoniazid Marketed formulation 153

9 I it Di l ti P fil f th F l ti F1 154


16/361

19. In vitro Dissolution Profile of the Formulations F9-INH Release 164




23. In vitro Dissolution Profile of the Formulations F9-RIFA Release 168




27.

Kinetic values obtained from in-vitro release data of different

dispersible formulations. Model fitting of the release profile using two

different models

172

28.

Kinetic values obtained from in-vitro release data of different

dispersible formulations. Model fitting of the release profile using three

different models

173

29.Kinetic values obtained from in-vitro release data of different

dispersible formulations: n value, k value, order of reaction174

30.Anti-Tubercular Activity of Isoniazid, Rifampicin and Combination

Dispersible Formulations.175


17/361

LIST OF FIGURES

TABLE

NO.TITLE

PAGE

NO.

1. Standard Calibration Curve of Isoniazid at 261 nm in PB 6.8 182

2. In vitro Dissolution Profile of the pure Isoniazid 183

3. In vitro Dissolution Profile of the Isoniazid Marketed formulation 184

4. In vitro Dissolution Profile of the Isoniazid Formulations F1 to F4

(Zero Order plot)

185


(First Order plot)

186


(Higuchi Matrix plot)

187


(Peppas plot)

188


(Hixson Crowell plot)

189

9. In vitro Dissolution Profile of the pure Rifampicin 190

10. In vitro Dissolution Profile of the Rifampicin Marketed formulation 191

11. In vitro Dissolution Profile of the Rifampicin Formulations F5 to F8 192


18/361


(Higuchi Matrix plot)

199


(Peppas plot)

200


(Hixson Crowell plot)

201

21. In vitro Dissolution Profile of the Rifampicin Formulations F9 to

F12 (Zero Order plot)

202

22. In vitro Dissolution Profile of the Rifampicin F9 to F12 (First Order

plot)

203

23. In vitro Dissolution Profile of the Rifampicin F9 to F12 (Higuchi

Matrix plot)

204


F12 (Peppas plot)

205


F12 (Hixson Crowell plot)

206


(Zero Order plot)

207

27. Pharmacokinetic Release Profile for Formulation F-1 208

28. Pharmacokinetic Release Profile for Formulation F-5 209

29 Pharmacokinetic Release Profile for Formulation F-9 210


19/361

LIST OF ABBREVIATIONS

INH Isoniazid

RIFA Rifampicin

FDT Fast disintegrating tablet

DDS Drug delivery system

FDT Fast disintegrating tablet

FDC Fixed dose combination

MDT Mouth dissolving tablet

UV Ultra violet Spectroscopy

et. al Co-author

ODT Oral dispersible tablets

MR Modified release

SEM Scanning electron microscopy

ICH International Conference on Harmonization


20/361

Chapter I Introduction

INTRODUCTION

Due to a society that is becoming increasingly aged, the development of an

appropriate dosage form for the elderly is most desirable. Because the changes in various

physiological functions associated with aging including difficulty in swallowing, current

dosage like capsule, are impractical.1

DISPERSIBLE DOSAGE FORMS:

Oral drug delivery is most widely utilized route of administration among all the

routes due to ease of ingestion, pain avoidance, versatility (to accommodate various types

of drug candidates) and most importantly patient compliance.2

One of the added

advantage of solid oral delivery system does not require sterile conditions and are

therefore less expensive to manufacture. Such type of oral drug delivery is most widely

utilized route of administration among all the routes that have been explored for systemic

delivery of drugs via pharmaceutical products of different of dosage form. The most

popular solid dosage forms being tablets and capsules, one important drawback of these

dosage forms for patient is the difficulty to swallow, especially the elderly and


21/361


porous tablets, mouth dissolving tablets, quick dissolving or rapidly disintegrating

tablets.5-6

When kept on tongue, upon ingestion, the saliva serves to rapidly dissolve the

dosage form. The saliva containing the dissolved or dispersed medicament is then

swallowed and the drug is absorbed. As the tablet, which disintegrates in the mouth, this

could enhance the clinical effect of the drug through pre-gastric absorption from the

mouth, pharynx and oesophagus as the saliva passes down in to the stomach. In such

cases, bioavailability of drug is significantly greater than those observed from

conventional tablet dosage form by avoiding first pass liver metabolism.7

The advantages of mouth dissolving dosage forms are increasingly being

recognized in both, industry and academia. Their growing importance was underlined

recently when European pharmacopoeia adopted the oro-dispersible tablet as a tablet to

be placed in the mouth where it disperses rapidly before swallowing. Despite

disadvantages, novel technologies with improved performance, patient compliance, and

enhanced quality have emerged in the recent past. Oral mouth dissolving dosage forms,

three-dimensional printing (3DP) and electrostatic coating are a few examples of a few

existing technologies with the potential to accommodate various physico-chemical,


22/361


The more sophisticated a delivery system, the greater is the complexity of these

various disciplines involved in the design and optimization of the system. In any case, the

scientific framework required for the successful development of an oral drug delivery

system consists of a basic understanding of the following three aspects.9-15

1. Physicochemical, pharmacokinetic and pharmacodynamic characteristic of drug

2. The anatomic and physiologic characteristics of the GIT

3. Physicochemical characteristics and the drug delivery mode of the dosage form to

be designed7

Desired criteria for mouth disintegrating drug delivery system:16-19

Fast-dispersible tablet should have characteristics such as:

Do not require water to swallow, but it should dissolve or disintegrate in the

mouth in the matter of seconds

Should have a pleasing mouth feel, Be compatible with taste masking

Be portable without fragility concern

Leave minimal or no residue in the mouth after oral administration

Exhibit low sensitivity to environmental condition i e humidity and temperature


23/361


Good mouth feels property of MDDS helps to change the basic view of

medication as bitter pill, particularly for pediatric patients

Rapid dissolution and absorption of drugs, which may produce quick onset of

action

Some drugs will absorbs from mouth, pharynx and oesophagus as the saliva

passes down in to the stomach; in such cases bioavailability of drugs is

increased

Ability to provide advantages of liquid medication in the form of solid form

Pre-gastric absorption can result in improved bioavailability and as a result of

reduced dosage, improved clinical performance through a reduction of

unwanted effects

Mechanism of action of oral dispersible tablets

Tablet Disintegration into

ordered unitsUnits adhere to the

sublingual mucosa

Carrier particle dissolve

and release the active


24/361


biotransformation of drugs through oxidation, reduction and hydrolysis. The drug

excreted by renal clearance is slowed, thus half-life of renal excreted drugs increased.

Pharmacodynamic: Drug receptor interaction are impaired in elderly as well as in

young ones due to the under development of organs.22

Decreased ability of the body to respond baroreflexive stimuli, cardiac output,

and orthostatic hypotension may seen in taking antihypertensive like prazocin

Decreased sensitivity of the CVS to -adrenergic agonist and antagonist

Immunity is less and taken into consideration while administered antibiotics

Altered response to drug therapy- elderly show diminished bronchodilator

effect of theophylline shows increased sensitivity to barbiturates

Concomitant illnesses are often present in elderly, which is also taken into

consideration, while multi-drug therapy is prescribed

The incidence of diabetes and glucose tolerance is well documented and hence

every attempt is made to avoid sugar-containing excipients

Increasing the number of medication results in more complex dosing interval,

d i d diffi lti i d f d i


25/361


Patient may suffer from tremors therefore they have difficulty to take powder and

liquids. In dysphagia physical obstacles and adherence to esophagus may cause

gastro-intestinal ulceration

Liquid medicaments (suspension, emulsion) are packed in multi-dose container;

therefore achievement of uniformity in the content of each dose may be difficult

Buccal and sublingual formulations may cause irritation to oral mucosa, so patient

refuses to use such medication

Cost of the product is main factor as parentral formulations are more costly

In transdermal drug delivery systems, there is an increase in rate of permeation

through aging skin but the permeated drug substances have slower rate of clearance

into general circulation which may lead to incomplete drug distribution

Formulation of Fast-dispersible tablets:

For rapid dissolution of dosage, water must rapidly penetrate into tablet matrix to

cause quick disintegration and instantaneous dissolution of tablet. Several techniques are

used to achieve these fundamentals to formulate Fast-dispersible tablet; like table

moulding freeze drying spray drying sublimation and addition of disintegrating agents


26/361


amount of water absorption. The simultaneous presence of disintegrant with high

swelling force called disintegrating agent and substances with low swelling agent are

claimed to be key factor for rapid disintegration of tablet; which also offer physical

resistance.

Sublimation:26-28

Low porosity prolonged dissolution even tablets containing highly water soluble

ingredients, inert solid ingredients that volatilize readily (camphor, ammonium

bicarbonate, ammonium carbonate, ammonium acetate, urea, urethane, naphthalene)

were mixed with other ingredients and then mixture compressed into tablets. Volatile

material is removed by subliming, which tends to produce porous structure. Compressed

tablets containing mannitol and camphor have been prepared by sublimation technique.

The tablets exhibit sufficient mechanical strength for practical use.

Tablet Moulding:29,30

By using water-soluble ingredients, moulded tablets are prepared. Powder is

moistened with the help of hydroalcoholic solvent and then moulded in to tablets under

l th ti l d f R l f l t i d b i d i


27/361


Freeze drying:31-36

A process in which water is sublimated from the product after freezing is called

freeze drying. Freeze dried forms offer more rapid dissolution than other available solid

products. The lyophilization process imparts glossy amorphous structure to the bulking

agent and some times to the drug, thereby enhancing the dissolution characteristics of the

formulation. However the use of freeze drying is limited due to high cost of the

equipment and processing. Other major disadvantages of the final dosage forms include

lack of physical resistance in standard blister packs.

The freeze-drying process consists of three phases.

1. Freezing to bring the material below its eutectic zone

2. Sublimation drying or primary drying to reduce moisture to around 4% w/w

of dry product

3. Desorption or secondary drying to reduce bound moisture to the required final

value

Spray drying:37-41

Spray drying can be used to prepare rapidly dissolving tablets. This technique is


28/361


blade to form tablets. The dried cylinder can also be used to coat granules of bitter tasting

drugs and thereby masking their bitter taste.

Patented technologies for mouth dissolving tablets:

Zydis technology:18

Zydis formulation is a unique freeze dried tablet in which drug is physically

entrapped or dissolved within the matrix of fast dissolving carrier material. When Zydis

units are put into the mouth, the freeze-dried structure disintegrates instantaneously and

does not require water to aid swallowing. The Zydis matrix is composed of many

materials designed to achieve a number of objectives. To impart strength and resilience

during handling, polymers such as gelatin, dextran or alginates are incorporated. These

form a glossy amorphous structure, which impart strength to obtain crystallinity,

elegance and hardness; saccharides such as mannitol or sorbitol are incorporated. Water

is used in the manufacturing process to ensure production of porous units to achieve rapid

disintegration. Various gums are used to prevent sedimentation of dispersed drug

particles in the manufacturing process. Collapse protectants such as glycine prevent

shrinkage of Zydis units during freeze drying process or long term storage. Zydis


29/361


Orasolve technology:37

Orasolve technology has been developed by CIMA labs. In this system active

medicament is taste masked. It also contain effervescent disintegrating agent. Tablets are

made by direct compression technique at low compression force in order to minimize

oral dissolution time, conventional blenders and tablet machine is used to produce the

tablets. The tablets produce are soft, friable and packed in specially designed pack and

place system.

Flashdose (fluisz technologies ltd.):37

Fluisz technologies has three oral drug delivery systems that are related to fast

dissolution, the first two generations of quick dissolving tablets, soft chew and floss

chew, require some chewing. This technology utilized a unique spinning mechanism to

produce floss like crystalline structure, much like cotton candy. This crystalline sugar can

then incorporate the active drug and can be compressed in to a tablet.

FLASHTAB (propharm group):37

The FLASHTAB technology is yet another fast dissolving/disintegrating tablet

f l ti it tili t f th i i t i ti l d t bl t


30/361


Oraquick (kv pharmaceutical company inc.):37

The Oraquick mouth dissolving tablet formulation utilized a patented taste

masking technology. KV pharmaceutical claims its microsphere technology, known as

micromask, has superior mouthfeel over taste masking alternatives. The taste masking

process does not utilize solvents of any kind, and therefore leads to faster and more

efficient production. Also lower heat of production than alternative fast dissolving

technologies make oraquick appropriate for heat sensitive drugs. Oraquick claims quick

dissolution in a matter of seconds, with good taste masking.

Shearform technology:42-44

The Shearform technology is based on preparation of floss that is also known as

shearform matrix, which is produced by subjecting a feedstock containing sugar carrier to

flash heat processing. In this process, the sugar is simultaneously subjected to create an

internal flow condition, which permits part of it to move with respect of the mass. The

flowing mass exits through the spinning head that flings the floss, the floss so produced is

amorphous in nature, which is further chopped and re-crystallized by various techniques

to provide uniform flow properties and thus facilitate blending.


31/361


and rapidly spinning machine. The centrifugal force of the rotating head of ceform

machine throws the drug blend at high speed through small, heated openings. The

carefully controlled temperature of the resultant microburst of heat liquefies the blend to

form a sphere without adversely affecting drug stability. The microsphere are then

blended and/or compressed into the pre-selected oral delivery dosage form. The ability to

simultaneously process both the drug and excipients generates a unique

microenvironment in which materials can be incorporated into the microsphere that can

alter the characteristics of the drug substance, such as enhancing solubility and stability.

The microsphere can be incorporated into a wide range of fast dissolving dosage forms

such as EZ chew, spoon dose as well as conventional tablets.

ROLE OF DISINTEGRANT:49

For tablets, it is necessary to overcome the cohesive strength introduced into the

mass by compression. Therefore, it is usual practice to incorporate excipients called

disintegrant, which will include during formulation. Tablets containing a disintegrant

break up rapidly in the water because of the sudden and immediate application of the

stress. However, when a tablet containing such disintegrant is exposed to water stress is


32/361


maintain a porous structure in the compressed tablet and show a low interfacial tension

based towards aqueous fluids. Rapid penetration by water throughout the entire tablet

matrix to facilitate its breakup is thus achieved. Concentrations of the disintegrants that

ensure a continuous matrix of disintegrant are desirable, and levels of between 5 to 20%

are common.

II) Disintegrants that swell:

One general problem with group of disintegrats is that on swelling, many

disintegrant produce a sticky or gelatinous mass that resist break up of the tablet, making

it particularly important to optimize the concentration present. Although untreated

starches do not swell sufficiently, certain modified forms, such as Sodium starch

glycolate, do swell in cold water and are better as disintegrant.

Some powdered gums, such as agar, karaya or Tragacenth swell considerable

when wet, but their pronounced adhesiveness limits their value as disintegrant and

restricts the maximum concentration at which they can be effectively used to

approximately 5% of the tablet weight.

III) G P d i Di i t t


33/361


mucilage) addition of small quantity of appropriate enzyme may be sufficient to produce

rapid disintegration.

Mechanism of action:50-51

Water Uptake:

Water uptake has been implicated as a mechanism of action for tablet disintegrats.

The ability of particles to draw water into the porous network of a tablet (wicking) was

essential for efficient disintegration. If wetting of the disintegrant particle showed,

disintegration of the tablet showed, thus extent of water uptake are both critically

important for a number of tablet disintegrants.

Swelling:

Perhaps the more widely accepted general mechanism of action for tablet

disintegration is swelling. Almost all disintegrants swell to some extent. And swelling

has been reported quite universally in the literature.

Deformation:

Plastic deformation under the stress of tableting has been reported for many years.


34/361


Particle Repulsion Theory:

Theory of the tablet disintegration attempt to explain the swelling of tablets made

with a non-swellable starch. A particle repulsion theory based on the observation that

particle do seem to swell but still disintegrate tablets was proposed. It was revealed that,

alteration in the dielectric constant of disintegrating media an effort to identify electric

repulsive forces as the mechanism of disintegration was successful, and the water was

required for tablet disintegration. Hence, repulsion is secondary to wicking, as the

primary mechanism of action for all tablet disintegrants.

Particle Size:

Physical characteristics of disintegrants, such as particle size, also have some

bearing on the mechanism of disintegration. (eg. Swelling and water uptake). Several

attempts have related the particle size of disintegrants to their efficiency. The effect of

particle size of starch grains on the ability to disintegrate tablets. Starch grains with

relatively large particles size were more efficient disintegrants then the finer grades.

Particle size plays a key role in the overall efficiency.

TUBERCULOSIS


35/361


tuberculosis.53

M. Tuberculosisis a slender, or slightly curved bacillus, ranging from 1-4

mlength, they are acid-fast bacilli.54

The therapeutic potential of Rifampicin in tuberculosis is well recognized due to

its unique ability to kill semi dormant tubercule bacilli (M. Tuberculosis). It is

categorized amongst first line agents including Isoniazid, Pyrazinamide, Ethanbutol and

Streptomycin which are used in combination as effective therapy for all forms of diseases

caused by M. Tuberculosis. WHO recommends a six month regimen comprising

Rifampicin, Isoniazid, Pyrazinamide and Ethanbutol which are given together for the first

two month followed by Rifampicin and Isoniazid therapy for the next four months.

Rifampicin is mainly eliminated in bile and then reabsorbed, hence enterohepatic

circulation ensues. During this time the drug is progressively deacylated into its

microbiologically active metabolite, 25-desacetyl Rifampicin which is less absorbable as

compared to the parent drug.55

Tuberculosis has a definitive affinity for the lungs causing primary disease.

However, any part of the body can be affected, including the mouth and normally these

lesions are secondary to lung disease.


36/361


ulcerative form is the most common and is often painful with no associated caseation of

the dependent lymph nodes.56

Reports have shown that oral lesions occur in 0.05-5% of the patients with

tuberculosis and frequently are secondary affecting more usually elderly patient. On the

other hand, the primary form more uncommon and more usually affects young patients.57

An attempt has been made, in the present work, to develop dispersible tablet of

Isoniazid, Rifampicin and their combination by direct compression methods, to increase

the bioavailability of the anti tubercular agents as well to provide the local delivery in the


37/361

Chapter II Need and Objectives

NEED AND OBJECTIVES

NEED

Fast disintegrating tablets are drug delivery systems with high acceptance and

compliance. The major advantage of fast disintegrating tablet is drug administration at

any time without water, self medication and stability compared to parenterals which

increased patient compliance.58

Due to disintegration of formulation in the mouth,

elimination of bitterness is important criteria in product formulation of mouth dissolving

tablets.59

Rifampicin, Isoniazid, Pyrazinamide and Ethambutol are the drugs of choice for

treating tuberculosis. Fixed dose combination of two, three or four drugs is a preferred

dosage form for efficient reduction in viable bacterial population and minimizing

development of resistance to anti-tubercular drugs.60

Isoniazid is a widely used antimycobacterial agent for first line therapy of

Tuberculosis (TB). The drug is characterized by a short half-life ranging from 1 h to 4 h,

depending on the rate of metabolism. INH is inactivated in liver, mainly by acetylation


38/361


systems. However, bioavailability of Rifampicin is significantly impaired when it is

administered along with Isoniazid as a Fixed Dose Combination (FDC).62-63

Difficulty in swallowing (dysphasia) is a common problem of all age groups,

especially the elderly and pediatrics because of the physiological changes associated

with these groups.4

Other categories that experience problems using conventional oral

dosage forms are the mentally ill, uncooperative and nauseated patients, those with

condition of motion sickness, sudden episodes of allergic attack or coughing.

Sometimes, it may be difficult to swallow conventional products due to unavailability of

water. These problems led to the development of novel type of solid oral dosage forms

called fast-dispersible tablets, which disintegrate and dissolve rapidly in saliva without

the need of drinking water. They are known as fast dispersible tablets, melt-in-mouth

tablets, rapimelts, porous tablets, mouth dissolving tablets, quick dissolving or rapidly

disintegrating tablets.4-5

The most desirable formulation to use by the elderly is one that is easy to swallow

and easily to handle. Oral dispersible formulation of the anti-tubercular drug, increase the

bioavailability of the anti-tubercular agents as well to provides the local delivery in the


39/361


OBJECTIVES

The study has been designed to develop the fast disintegrating formulations of

Isoniazid, Rifampicin and its combination which would enhance absorption and

bioavailability of the drugs. It includes selection and optimization of the suitable

excipients such as superdisintegrants for development of fast disintegrating tablet for the

treatment of the tuberculosis. Following specific aims were set to achieve the above

stated objective.

1) Preparation of standard calibration curve for Isoniazid and Rifampicin

2) Formulation development of fast disintegrating tablet by direct compression method

3) Characterization and evaluation of the formulations

I. Pre-compression parameter:

a. Drug excipient compatibility studies: Comparison of drugs and its

combination with various polymers by FTIR

b. Evaluation of powder: Angle of repose, compressibility index

II. Post-compression parameters:

a Appearance and its dimension measurements


40/361


4) In vitroevaluation of formulations

a. In vitrodispersion studies

b. In vitrodisintegration studies

c. In vitrodissolution studies and curve fitting analysis

d. Microbiological screening of formulations

e. Stability studies and shelf life determination of the selected formulations

5) In vivostudies

a. In vivopharmacokinetic studies for selected formulations

b. In vitro-In vivo correlations (IVIVC)


41/361

Chapter III Review of Literature

REVIEW OF LITERATURE

Drug Review:

Isoniazid

Isonicotinylhydrazid; INH

N

CONHNH2

C6H7N3O Mol. Wt. 137.14

Isoniazide is Isonicotinohydrazide.

Category: Antitubercular

Dose: 300mg daily or up to 1g twice weekly.

Description: Colourless crystals or white, crystalline powder; odourless.

Solubility: Freely soluble in water; sparingly soluble in ethanol (95%); slightly

soluble in chloroform; very slightly soluble in ether.

Storage:

Store in well-closed, light- resistant containers.


42/361


Isoniazid given in the initial and continuation phase of short- course tuberculosis

regimens. The usual adult dose is 300 mg daily by mouth on an empty stomach.

Childrens dose varies between 5 mg per body-weight daily. All with the maximum of

300 mg daily.

Similar doses to those used orally may be given by Intramuscular injection when

Isoniazid cannot be taken by mouth; it may be also given by Intravenous injection.

Isoniazid has also given Intrathecally and Intrapeleurally.

In tuberculosis prophylaxis, daily doses of 300 mg are given at least 6 months and

sometimes for up to 1 year. Alternatively it may be given with Rifampicin for 3 months.

Doses of 5 to 10mg per kg Isoniazid daily to a maximum of 300mg daily have been

suggested for prophylaxis in children in the UK.

Preparations:

BP 1998:Isoniazid injection, Isoniazid Tablets;

USP 23:Isoniazid injection, Isoniazid Tablets, Isoniazid Syrup, Rifampicin and

Isoniazid capsules.61, 64, 65

Past work done on Isoniazid:


43/361


heterogeneous with the maximum particle of an average size of 3.719m. They conclude

that the mean particle size of the microspheres increased with an increase in the

concentration of polymer and the cross-linker as well as the cross- linking time.66

Maria SM and Angnes Lproposed a new, fast and precise method to analyze

Isoniazid based on the electrochemical oxidation of the analyte at glassy carbon electrode

in 0.1M NaOH, quantification was performed by utilizing Amperometry associated with

the batch injection analysis (BIA) technique. Fast sequential analysis in an unusually

wide dynamic range with high sensitivity and low limit of detection and quantification

was achieved. They concluded that such characteristics allied to a good reproducibility of

the current responses for the specific determination of Isoniazid in Isoniazid- Rifampicin

tablet.67

Gursoy A, et al, Co-encapsulated the INH and RIF in the same liposome

formulation, INH was incorporated in the aqueous phase and RIF in the lipid layer;

separate liposome formulation of INH and RIF was also prepared. All the liposome

formulations were compared for their loading capacity, encapsulation percentage and

release properties, drug amounts in the liposomes were estimated using peak-to-peak first


44/361


clinically insignificant. They concluded that FDC formulation is bioequivalent for

Rifampicin, Isoniazid and Pyrazinamide and ensure the successful treatment of TB

without compromising therapeutic efficacy of any of these components of anti-TB

therapy.69

Singh S et al,Determined the behavior of moisture gain by four anti-tuberculosis

drugs, viz. Rifampicin, Isoniazid, Pyrazinamide and Ethambutol, when exposed in pure

form and in combinations to accelerated conditions of 40C and 75% RH, in the absence

and the presence of light, weight gain was seen only in those samples that contained

Ethambutol, and this behavior was observed in both in dark and lighted chambers. They

observe decrease in moisture uptake with an increase in the number of drugs in the

mixture. They also observed that higher weight gain by the mixture of Ethambutol and

Isoniazid in a dark chamber, then either pure Ethambutol or drug combinations

containing Ethambutol. They concluded that an overall acceleration of weight gain in the

presence of light as compared with dark conditions.70

Agarwal S and Punchagnula Rdeveloped a dissolution methodology to predict

in vivo performance of Rifampicin containing FDC (INH) products. Six FDC


45/361


RIFAMPICIN

Formula: C43H58N4O12 Mol. Wt. 822.95

Rifampicin is (12Z,14E,24E)-(2S,16S, 17S, 18R, 19R, 20R, 21S, 22R, 23S)- 1,2 dihdro-

5.6.9, 17, 19- heptamethyl-8-(4-methyl-peprazine-1-yliminomethyl)-1,11,13-

triemino)neptho[2,1-b] furan 21-yl acetate.

Category: Antitubercular.

Dose: for an adult, 450 to 600 mg (about 10mg per kg) daily preferably before breakfast.

For child, up to 20mg per kg daily to a maximum of 600 mg.

Description: Brick-red to reddish brown, crystalline powder; practically odourless.

Solubility: Soluble in chloroform and in methanol; slightly soluble in acetone, in

ethanol, in ether, in water.


46/361


in the liver mainly to active desacetylrefampicin; rifampicin and desacetylrefampicin are

excreated in the bile.

Uses and administration: Rifampicin belongs to the rifamycin group of

antimycobecterial and is used in the treatment of various infections due to mycobecteria

and other susceptible organisms. It is usually given combined with other antibacterial to

prevent the emergence of resistant organisms.

Preparations:

BP 1998:Rifampicin capsule, Rifampicin oral suspension.

USP 23: Rifampicin and Isoniazid capsule; Rifampicin capsule, Rifampicin or

injection; Rifampicin oral suspension.62,72,73

Past work done on Rifampicin:

Singh S et al (2002) determine the behavior of moisture gain by four anti-

tubercular drugs, viz. Isonaizid, Rifampicin, Pyrazinamid, Ethambutol, when exposed to

the pure form and in combination to accelerated condition of 40Cand 75%RH, in

presence and absence of light. Weight gain was observed only in those samples that

contained ethambutol, and the behavior was observed both in dark and in lighted


47/361


Panchagnula R et al investigate the effect of food on the bioavailability of

Rifampicin from anti-tubercular fixed dose combination formulations. They assessed the

effect of hydrodynamic stress in presence of food and meal composition on 2 Rifampicin

containing fixed dose combination formulations by carrying out dissolution at different

agitation rates (Simulation of fasted and fed state) as well as presence of different

percentage of oil (fatty food). Agitation intensity as well as presence oil did not had any

influence on Rifampicin release from formulation A. they concluded food may not has

have any effect on the release of Rifampicin from the formulation and subsequently on its

bioavailability if the formulation has excellent release profile( > 85% release in 10 min.),

further. Effect on food on the Rifampicin release was a function of dosage form

characteristics such as disintegration time and dissolution rate, which will subsequently

affect the release behavior of the formulation in presence of food.76

Rao BS et al (2001) investigate the possibility to develop different levels of

correlation between in vitro dissolution parameters and in vivo pharmacokinetic

parameters for three Rifampicin formulations. A level A correlation of in-vitro

dissolution and in-vivo absorption could be obtained for individual plasma level data by


48/361


Lalla JK, et al, (2004) prepared fast dissolving Rofecoxib tablets by forming

inclusion complexes between Rofecoxib and -cyclodextrin using ball mill technique and

evaluated by using DSC technique. Tablet disintegration times were in the range of 30-

40s. The dissolution study indicates either wet or dry granulation, which showed

complete release of drug. Rofecoxib tablets showed complete release in 12 min as

compared to 12% drug release from conventional marketed tablets during same period.79

Kuchekar BS, et al., (2004) prepared Sumatriptan succinate mouth dissolving

tablets using disintegrates such as sodium starch glucolate, carboxy methylcellulose

sodium, and treated agar by direct compression method. The prepared tablets were

evaluated for various parameters. The tablet disintegration in-vitroand in-vivowas found

to be 10 to 16 sec respectively. The formulations containing combination of sodium

starch glycolate and carboxy methylcellulose was found to be giving best result.80

Mukesh G, et al, (2004) Formulated, designed and optimized the mouth

dissolving tablets of Nimesulide using vacuum drying technique. Granules were prepared

by using camphor and crospovidone, and then exposed to vacuum for camphor

sublimation and compressed. Alternatively next tablets were first prepared and then


49/361


Fahum, et al, (2004)Invented orodispersible tablets containing Fexofenadine in

the form of coated granules and mixture of excipients comprising of at least one

disintegrating agent, a lubricant and organoleptic additives.the granules posses all

pharmaco-technical property.83

Amin PD, et al, (2004)Prepared the fast disintegrating dosage form of Oflaxacin

and Metronidazole benzoate. They optimized the process of taste masking with respect to

parameters like time required for complexation, percentage loading and volume required.

They showed that the ion exchange resins could be successfully used, as both taste

masking agent and superdisintegrants.84

Abdelbery G, et al, (2005) determined the in-vivo disintegration profile of

rapidly disintegration tablets and correlation with oral disintegration with the use of the

texture analyzer. They have shown in their study that the obtained time-distance profile

or disintegration profile and calculated values reflected the mechanism of disintegration

of different RDT and gave a qualitative measure of their mouth feel.85

Patravale VB, et al, (2005) Focused on the quinine sulphate having bitterness

threshold of 0.0007% indicating its intense bitter taste. They developed the process for


50/361


min in the case of formulation containing 3% and 5% of Ac-Di-Sol and polyplasdone

showed 91.89 %and 101% release respectively in 12 min.87

Mahayana HS, et al, (2000) developed the rapidly disintegrating tablets for

elderly patients and they concluded that rapidly disintegrating tablets can be prepared by

conventional direct compression method using superdisintegrants which show rapid rate

of disintegration and alternate form of oral medication for elderly.88

Mizumoto T et al, (2005) designed the formulation of novel fast disintegrating

tablets as a user-friendly dosage form for the aged using Acetaminophen as a model drug.

Mannitol and lactose were used as the low compressibility saccharide and maltose as the

high one and as the binder for granulation. Aspartame and Menthol flavor were used as a

taste masking for the bitter teste of Acetaminophen.89

A new approach to prepare RDT with sufficient mechanical integrity was

proposed by Abdelbary A. et al(2004), involving the use of a hydrophilic waxy binder

(superpolystate) PEG-6- stearate). Superpolystate) PEG-6- stearate act as a binder and

increased the physical resistance of tablet but will also help the disintegration of tablets

as it melt in the mouth and solublises rapidly leaving no residues. Scanning electron


51/361


compression force. The calculation models are used to assess the crushing strength and

prolong tablet disintegration, the L-leucine concentration is kept at a low level.91

Shicheng Y. et al(2004) used poly (acrylic acid) as a wicking agent to decrease

disintegration time of fast disintegrating tablets (FDTs). Compression behavior of poly

(acrylic acid) SPH microparticals was evaluated by Kawakita equation. They observe the

effect of various SPH microparticals size and a 19 run fractional factorial design. The

factorial design based on four factors consisting Ketoprofen, SPH, micropartical and

tableting pressure, and each factor contained three levels on the disintegration time and

tensile strength of the prepared FDTs. The compressibility of SPH microparticals

increased significantly as the microparticals size increased. They concluded poly (acrylic

acid) SPH microparticals could serve as a good Super-disintegrent decreasing the

disintegration time of FDTs.92

Panday VP et al (2007) formulated dispersible tablets of Solbutamol sulphate as

paediatric dose. They used dry granulation method for the formulation of Solbutamol

dispersible tablets and evaluate other pharmacopoeial and non- Pharmacopoeial

specifications. They concluded that the formulated tablets are stable, safe and patient


52/361


that formulated formulations fulfill all official requirements and gave fast and rapid

dissolution of drug.95

Madukar AR et al (2007) studied the efficiency of Indion 414 and Amberlite

IRP 88 as superdisintegrent in mouth dissolve tablets. The Nimuslide dispersible tablets

with Indion 414 and Amberlite IRP 88 were prepared and evaluated for disintegration

effect. The concluded that Indion 414 was found to be better superdisintegrants.96

Chebli C and Cartilier L (1998) evaluated properties of a new tablet

binding/disintegrating agent, cross-linked cellulose (CLC) in comparision with other

binding/disintegrating agents widely used in tablet manufacturing such as Avicel PH101

and Avicel PH 102, as well as with superdisintegrents known for their high efficiency

such as Ac-di sol and Explotab. CLC C25 was obtained y simple reaction of cellulose

with epichlorohydrin in strong basic medium. The effect of CLC-C25 concentration on

particle properties of direct compression tablets was also studied. CLC-C25 demonstrated

good binding/disintegrating agents97

.

A rapidly disintegrating tablet in oral cavity was prepared using glycine as a

disintegrant by Fukami J et al(2006). They determine the effect of disintegrant on the


53/361


Patel MM and Patel DM(2006) prepared and evaluated Valdecoxib Fast

dissolving tablets containing solid dispersion of Valdecoxib. Solid dispersion of

Valdecoxib with mannitol, polyethylene glycol 4000, and polyvinylpyrrolidone K-12

were prepared with a view to increase its water solubility. The formulation was found to

be stable for 4 weeks at 45, with insignificant change in the hardness, disintegration time

and in vitro drug release pattern100

.

Adamo F et al (2008) developed fast dispersible and slow release Ibuprofen

tablets. To prevent bitter test and side effect of the drug, the drug is associated with

Phosphophlipon 80H, a saturated lecithin by wet granulation. The granules were then

formulated with sweetener (Aspartame), a mannitol-based diluent( pearlitol SD200) and

Kollidon CL(1-4K) were added as added as superdisintegrants and compacted under low

compression force. They concluded an appropriate combination of excipients it is

possible to obtain orally disintegarating tablets and a delayed release of ibuprofen using

simple and conventional technique101

.

Chandrashekhar R et al(2009)evaluated the role of formulation excipients in

the development of lyophilized fast-disintegrating tablets, using a progressive three-stage


54/361


Shukla V et al(2008)prepared and evaluated Clozapine dispersible tablets, using

different superdisintegrants such as Ac-di-Sol, Polyplastadone XL, Explotab for the

effective management of Schizopherenia. The tablets were prepared by direct

compression and sublimation method. The prepared formulations showed acceptable

pharmaco-technical properties. They concluded the mouth dissolving tablets could be a

promising drug delivery system for Clozapine with good mouth feel and improved drug

availability with better patients compliance104

.

Balasubramanium J et al(2008) studied the effect of selected superdisintegrants

on the dissolution behavior of several cationic drugs with varying water solubility. All

formulations were made with fixed disintegrant concentration and equal drug load using

a model formulation. Tablets were formulated by direct compression and were

compressed to equal hardness. They conclude crospovidone can be effectively used as a

tablet disintegrant to improve the dissolution of either soluble or poorly soluble cationic

drugs105

.

Seong HJ and Park K (2008) studied the complex formation between drugs and

ion change resin and the effect of coating by various aqueous polymeric dispersions on


55/361


Polyplastadone XL, Kollidon CL) in term of physiological properties and use in direct

compression and wet granulation. They conclude particle size distribution of

Polyplastadone XL is broader, and the swelling volume is bigger then those of Kollidon

CL. Kollidon F and SF grades had a substantially smaller particle size then Kollidone

CL and Polyplastadone XL and showed higher swelling volumes and hydration

capacities107

.

Profile of polymer and excipients used

MICROCRYSTALLINE CELLULOSE (Avicel PH 102) :108

Nonproperietary Name:

NF : Microcrystalline cellulose.

USP : Microcrystalline cellulose.

Functional Category: Tablet and capsule diluent, tablet disintegrant, suspending

and/or viscosity increasing agent.

Synonyms: Cellulose gel, Crystalline cellulose, Avicel PH 101,102,

Chemical names: Cellulose


56/361


Description: Purified, partially depolymerized cellulose occurs as a white, odorless,

tasteless, crystalline powder composed of porous particles.

Density:

Apparent density- 0.28g/cm3

Tap density- 0.43g/cm3

Solubility: Insoluble in water, dilute acids and most organic solvents, slightly soluble in

5% w/v NaOH solution.

Stability and Storage Conditions: Stable and hygroscopic. Store in a well closed

container.

Incompatibilities:None cited in the literature.

Safety: Generally regarded as safe.

Applications:

Tablet binder/diluent (wet or dry granulation) 5 to 20%

Tablet disintegrant 5 to 15%

Tablet glidant 5 to 15%

Antiadherent 5 to 20%


57/361


Description:Cross linked sodium carboxymethylcellulose White, free flowing powder

with high absorption capacity. Contains no sugar or starch.

Solubility: Easily Dispersed in Water

Stability and storage conditions: Crosscarmellose sodium is a stable though

hygroscopic material. Crosscarmellose sodium should be stored in a well-closed

container in a cool, dry, place.

Safety: It is inert and nontoxic.

Applications in pharmaceutical formulation:Crosscarmellose sodium is used in oral

pharmaceutical formulations as a disintegrant for Capsules, Tablets and Granules. In

tablet formulations, Crosscarmellose sodium may be used in both direct-compression and

wet-granulation processes.

CROSSPOVIDONE (Polyplasdone XL):108

Nonproprietary names:

USP: Povidone

BP: Povidone

F ti l t S di i t t t bl t bi d di i it


58/361


Solubility:Readily soluble in water up to 60%. Freely soluble in many organic solvents.

Storage conditions: Store in a moisture-proof, tight container to prevent decomposition

Safety: It is inert and nontoxic.

Applications in pharmaceutical formulation: As a superdisintegrant, carrier for drugs,

dispersing agent, tablet binder and as a diluents.

SODIUM STARCH GLYCOLATE (Explotab):108

Non-Proprietary Name:

NF: Sodium starch glycolate

BP: Sodium starch glycollate

Functional Category: Tablet disintegrant, Tablet and capsule disintegrant

Synonyms: Sodium carboxy methyl starch; Explotab; Primojel

Chemical Names: Starch carboxymethyl ether, Sodium Salt

Structural Formula:

CH OH

CH2O-CH

2COONa

CH OH


59/361


Incompatibilities:No citations found.

Applications in Pharmaceutical Formulation or Technology: It is used in

tablet/capsule as disintegrant (wet granulation or direct compression) in concentration

range 2-10%

KOLLIDON CL110

Nonproprietary names:

USP: Kollidon 12

BP: Kollidon 12

Functional category: As a superdisintegrant, Tablet binder, suspending or

viscosity increasing agent, sweetening agent

Synonyms: Povidonum, Povidon(e).

Chemical name: Polyvinylpyrrolidone, povidone

CAS Registration No: 9003-39-8

Empirical formula: (C6H9NO)n

Molecular weight: 2,000 to 15,00,000.


60/361


Applications in pharmaceutical formulation: The main function is as super-

disintegrant in tablets to fasten disintegration and dissolution. Like the soluble products

crospovidone improves the bioavailability of some hardly soluble actives.

CAMPHOR:109

Synonyms: Gum Camphor

CAS Registration No: 76-22-2

Molecular Weight: 152.24

Chemical Formula: C10H16O

Chemical name: Bicyclo [2,2,1] heptan 2-one, 1,7,7-trimethyl-camphor 2-

bornanone

Structure:

CH3CH3

CH3 O


61/361


Melting point: 176 to 180 C

Application: As a rubefacient, as a plasticizer for cellulose esters and ethers, explosives

and pyrotechnics, as a moth repellent, as a preservative in pharmaceuticals and

cosmetics.

MANNITOL:108


USP: Mannitol

BP : Mannitol

Functional category: Tablet and capsule diluent, sweetening agent, tonicity

agent, vehicle (bulking agent) for lyophilized preparations.

Synonyms: Mannite; manna sugar; manita.

Chemical name: 1,2,3,4,5,6 Hexanehexol.

CAS Registry Number : 69-65-8.

Empirical formula: C6H14O6

Molecular weight: 182.17

St t l F l


62/361


Bulk : 0.401 g/cm3

Tapped : 0.58 g/cm3

Solubility: Freely soluble in water, practically insoluble in ether.

Stability and Storage conditions: Mannitol is stable in dry state and in aqueous

solutions. In solution it is not attacked by cold, dilute acids or alkalies, not by

atmospheric oxygen in the absence of catalysts. No special storage conditions are

required. Store in a well closed container.

Incompatibilities:None reported in dry state. Mannitol is incompatible with a xylitol

infusion and forms complexes with metals like Fe, Al and Cu

Safety: When consumed orally in large quantities laxative effects may occur. Daily

ingestion of over 20 G is foreseeable.

Applications: As a diluent in tablets (10-90% w/w). It is not hygroscopic and can be

used with moisture sensitive active ingredients. In the manufacture of chewable tablet it

is used because of its negative heat of solution, sweetness and mouth-feel.

SACCHARIN SODIUM:108


63/361


Structural formula:

S

N

O O

O

-Na+

Description:

It is white, odorless or faintly aromatic, crystalline powder with an intensely

sweet taste.

Solubility:soluble in water and ethanol.

Stability and storage conditions: Store in an airtight container

Safety:estimated acceptable temporary daily intake up to 2.5 mg kg of body weight.

Applications in pharmaceutical formulation: As a sweetening agent, as a sugar

substitute in preparations for diabetics

MAGNESIUM STEARATE:108


NF : Magnesium stearate.

BP/EP: Magnesium stearate.


64/361


Description: It is a fine, white, precipitated or milled, impalpable powder of low bulk

density, having a faint characteristic odor and taste. The powder is greasy to touch and

readily adheres to the skin.

Density (He) : 1.03-1.08 g/Cm3

Bulk volume : 3.0-8.4 ml/g

Tapped volume: 2.5-6.2 ml/g

Solubility: Practically insoluble in ethanol, ethanol (95%), ether and water, slightly

soluble in benzene and warm ethanol (95%).

Stability and Storage Conditions: Stable, non-self polymerizable. Store in a cool, dry

place in a well closed container.

Incompatibilities: Incompatible with strong acids, alkalies, iron salts and with strong

oxidizing materials.

Safety: Described as inert or nuisance dust. OSHA has adopted limits of 15mg/m3for

the total dust and 5mg/m3for the respirable fraction. Dust clouds of magnesium stearate

may be explosive. However, oral consumption of large quantities may result in some

laxative effect or mucosal irritation.


65/361


Chemical names: Hydrous magnesium silicate.

CAS Registry number: 14807-96-6

Empirical formula: Mg6(Si2O5)4 (OH)4

Description: A very fine, white to greyish white, impalpable, odorless crystalline

powder, unctuous; adheres readily to skin; soft in touch free from grittiness.

Density:

Loose, CTFA-C8-1 : 19-24 lb/ft3

Tapped, CTFA-C7-1 : 48-62.5 lb/ft3

pH (1:5 dilution) :6.5-10

Solubility: Insoluble in water, Organic solvents, cold acids and dilute alkalis.

Stability and Storage Conditions: Stable. Preserve in a well closed container.

Incompatibilities: Quaternary ammonium compounds

Safety: Should not be applied to open wounds or used on surgical gloves. Prolonged and

intense exposure to talc may produce pneumoconiosis. Talc should not be inhaled.

Applications:

Lubricant in tablet and capsule - 1-4%

i l d h d


66/361

Chapter IV Materials and Methods

MATERIALS AND METHODS

MATERIALS:

The following materials that were either AR/LR grade or the best possible pharma

grade available were used as supplied by the manufacturer.

S. No. MATERIALS GRADE Manufacturer

1. Isoniazid IP Macloads Pharma. Ltd, Mumbai,

India

2. Rifampicin IP Macloads Pharma. Ltd, Mumbai,

India

3. Avicel pH 102 (MCC) Pharma Signet chemical, Mumbai

4. Kollidon CL Pharma Gujarat Microwax Ltd, Indore

5. Ac-di-sol Crosscarmellose) Pharma FMC biopolymer, USA

6. Cellosol (Crosscarmellose) Pharma Gujarat Microwax Ltd, Indore

7. Polyplasdone XL

(Crosspovidone)

Pharma Sun pharma, Mumbai

8. Explotab (SSG) Pharma Forum bioscience, England (U.K.)

9. Camphor L.R. S.D. Fine-Chem Ltd., Mumbai,

M i l d M h d


67/361


S. No. MATERIALS GRADE Manufacturer

17. Potassium dihydrogen

orthophosphate

L.R. Ranbaxy Fine Chemicals Ltd., New

Delhi, India

18. Di-potassium hydrogen

orthophosphate anhydrous

L.R. S.D. Fine-Chem Ltd., Mumbai,

India

19. Acetone L.R. S.D. Fine-Chem Ltd., Mumbai,

India

20. Potassium bromide (KBr) L.R. S.D. Fine-Chem. Ltd., Mumbai

EQUIPMENTS AND ACCESSORIES:

S. No. Name Manufacturer

1. Afcoset Electronic Balance The Bombay Burmah Trading Corp. Ltd.,Bombay, India

2.Hydraulic / Pellet Press Type-

WT

Kimaya engineers, Pokharan Road-I,

Upwan, Thane-400606, India

3. Monsanto Hardness tester Campbell electronic, Bombay

4. Friability Test Apparatus Campbell Electronics, Bombay, India.

5. Dial Caliper Mututoyo, Japan

6 Di i t ti t t t El t l b

h M i l d M h d


68/361


METHODS:

1) Preparation of Standard Calibration Curve:

Drug 1 Isoniazid

Standard Curve for Isoniazid:111

The standard curves for Isoniazid were prepared in distilled water, phosphate

buffer (pH 6.8) and methanol. Accurately 100 mg of Isoniazid were dissolved in 100 ml

of three different solvents such as distilled water, phosphate buffer (pH 6.8) and

methanol respectively. 1 ml of each of these solutions was diluted to 100 ml with distilled

water, phosphate buffer pH 6.8 and methanol respectively. The resulting stock solutions

were diluted to 10 ml with their respective solvents to give Isoniazid solution of 2, 4, 6,

8, 10 g/ml concentration. The absorbance of prepared solutions of Isoniazid in distilled

water, phosphate buffer (pH 6.8) and methanol were measured individually at max263

nm, 261 nm and 267 nm respectively, in UV Shimadzu spectrophotometer against the

respective medium as blank.

The absorbance data for standard curves are given in Tablet no. 2. Standard curve

Ch IV M t i l d M th d


69/361


their respective solvents to give Rifampicin solution of 2, 4, 6, 8, 10 g/ml concentration.

The absorbance of prepared solutions of Rifampicin in distilled water, phosphate buffer

(pH 6.8) and methanol were measured at max 256 nm, 333 nm and 244 nm respectively,

in UV Shimadzu spectrophotometer against the respective medium as blank.

The absorbance data for standard curves were given in Tablet no. 2. Standard

curve follow the Lambert-Beers Law in concentration range of 1-10 g/ml. All the

readings were taken in triplicate.

2) Formulation Development of Fast Disintegrating Tablets:

Direct Compression Technique:113-114

The vast majority of medicinal agents are rarely so easy to tablet, however in

addition, the compression of a single substance may produce that do not disintegrate. If

disintegration is the problem, other component are needed, which in turn may interfere

with the compressibility of the active ingredient and thus minimize the usefulness of the

method. Most materials posses relatively weak intermolecular attraction or are covered

with films of adsorbed gases that tend to hinder compaction. Thus, most large-dose drugs

d l d h l hi Wi h h d h i ll d

Ch IV M t i l d M th d


70/361


disintegrate, and inexpensive. Even through direct compression has some important

advantage there are some limitations to the technique.

1. Differences in particle size and bulk density between the drug and diluent may

lead to stratification within the granules. The stratification may then result in poor

content uniformity of the drug in the compressed tablet. The stratification and

resultant content uniformity are problems of special concern with low dose drugs.

2. A large dose drug may present problems with direct compression if it is not easily

compressible by itself. To facilitate compression, non-compressible large dose

drugs, which are usually restrict to about 30% of a direct compression formula,

could require an amount of diluent so large that the resultant tablet is costly and

difficult to swallow.

3. In some instances, the direct compression diluent may interact with the drug. A

good example of such a reaction is that which occurs between amine compounds

and spray dried lactose, as evidenced by a yellow discoloration.

4. Because of the dry nature of direct compression, static charge build up can occur

on the drug during routine screening and mixing, which may prevent uniform

Ch t IV M t i l d M th d


71/361


(Isoniazid, Rifampicin) as a model drug were evaluated. Rifampicin and Isoniazid are the

drugs of choice for treating tuberculosis. Fixed dose combination of two, three or four

drugs is a preferred dosage form for efficient reduction in viable bacterial population and

minimizing development of resistance to anti-tubercular drugs. The lower dose

combination formulations of Isoniazid and Rifampicin were formulated to identify the

possible cause for the significant impaired bioavailability of Rifampicin in Fixed Dose

Combination (FDC).

Ch t IV Materials and Methods


72/361


blended to get a uniform mixture in a geometrical order. The tablets were then

compressed using 10 mm size punches to get a tablet of 100 mg Isoniazid using hydraulic

press with suitable standard punches and stored in a well-closed container till use. In the

first set 4 batches of Isoniazid fast dispersible tablets were prepared using different

concentration of sodium starch glycolate and other super disintegrants.

Method of Preparation of Rifampicin Dispersible Tablets:

In experimental batches the total weight of Rifampicin was kept constant i.e. 100

mg. The optimum concentration of disintegrant was selected based on its concentration

required to disintegrate tablet within 3 minutes under experimental formula and

conditions of preparation. A total of 4 formulations were prepared. All the ingredients

were passed through 60 mesh sieve separately and collected. The Rifampicin and Avicel

pH 102 were mixed in a small portion of both and each time blended to get a uniform

mixture in a geometrical order. The tablets were then compressed using 10 mm size

punches to get a tablet of 100 mg uniform weight using hydraulic press with suitable

standard punches and stored in a well-closed container till use. In the first set 4 batches

of Rifampicin fast dispersible tablets were prepared using different concentration of

Ch t IV Materials and Methods


73/361


time blended to get a uniform mixture in a geometrical order. The tablets were then

compressed using 10 mm size punches to get a tablet of 100 mg uniform weight using

hydraulic press with suitable standard punches and stored in a well-closed container till

use.

In the first set 4 batches of Isoniazid and Rifampicin combination fast dispersible

tablets were prepared using different concentration of sodium starch glycolate and other

super-disintegrants.

3) Characterization and Evaluation of the Formulations:

(a) Precompression parameters:115

(i) Drug Excipient Compatibilities Studies:

The compatibility of drug and polymers under experimental condition is

important prerequisite before formulation. It is therefore necessary to confirm that the

drug does not react with the polymer and excipients under experimental condition and

should not affect the shelf life of product. This is confirmed by Fourier Transform

Infrared Spectroscopy (FTIR). It is a powerful technique for functional group



74/361


very important parameter to have good content uniformity within the developed

formulations. Angle of repose is the maximum angle possible between the surface of a

pile of powder or granules and the horizontal plane. It is calculated from the following

equation:

tan = h/r

= tan-1

(h/r)

Where, = angle of repose, h = height and r = radius

The fixed weight of granules was allowed to flow through the funnel fixed to a

stand at definite height. The angle of repose was then calculated by measuring the height

and radius of the heap of granules formed.

(iii) Bulk density:

The accurately weighed amounts of granules were taken in 25 ml measuring

cylinder. Volume of granule packing was recorded before tapping thereafter measuring

cylinder containing granule was tapped 100 times on a plane hard wooden surface and

tapped volume of packing recorded. Both loose bulk density (LBD) and tapped bulk



75/361


(b) Post compression parameters:

1. Appearance:

116

Uncoated tablets were examined under a lens for the shape of the tablet and

colour was observed by keeping the tablets in light.

2. Dimension:116

Thickness and diameter were measured using a calibrated dial caliper. Three

tablets of each formulation were picked randomly and dimensions determined.

3. Hardness test:116

Hardness indicates the ability of a tablet to withstand mechanical shocks while

handling. The hardness of the tablets was determined using Monsanto hardness tester. It

is expressed in kg/cm2. Three tablets were randomly picked and analyzed for hardness.

The mean and standard deviation values were also calculated.

4. Friability test:117

The friability of tablets was determined using Roche Friabilator. It is expressed in



76/361


Pharmacopoeia. The following percentage deviation in weight variation is allowed. In all

formulations, the tablet weight is less than 324 mg, hence 7.5 percentage deviations are

allowed.

Average weight of a tablet Percentage deviation

130 mg or less 10

>130 mg and


77/361


Petridish (i.d=6.5 cm)

Tablet

Tissue Paper

10.75 cm

1 2

c m

Tissue Paper

Simple Method for the Measurement of Wetting Time of a Tablet

8. Water absorption ratio:115

A piece of tissue paper folded twice was placed in a small petridish containing 6

ml of distilled water. A tablet was put on the paper and time required for complete

wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R,

was determined using equation:

10

)(

Wb

WbWa

R

Where, Wb = weight of the tablet before water absorption



78/361


determined according to US Pharmacopoeia monograph for tablet disintegration testing,

using the Electrolab tablet disintegration apparatus. The disintegration time was defined

as the time necessary for the fast disintegration formulations to completely disintegrate

until no solid residue remains. Phosphate buffer pH 6.8 (simulated saliva fluid)

maintained at 37 2

C as the immersion liquid. The temperature of the medium was

constantly monitored with thermometer. A digital stopwatch was used to measure the

disintegration time to the nearest second. Only one tablet was analyzed at a time in order

to ensure maximum accuracy. At the end of each test, the basket rack assembly and the

plastic disk were thoroughly washed and dried to remove any trace of tablet excipients

and water. A total of six tablets were tested from each batch, the values reported are

mean standard deviation. The in-vitro disintegration time of tablet was determined

using disintegration test apparatus as per I.P. specifications.

11.In vitrodissolution studies:123,124,125

Dissolution has emerged as a simple, rapid, and sensitive tool to judge the quality

of formulations. Based on the sound scientific principals of BCS, observed in vivo



79/361


to batch. Drug release obtained from formulations of different batches are bioavailable

and clinically effective.

Dissolution test for Isoniazid dispersible formulations:

The following procedure was employed throughout the study to determine the in

vitro dissolution rate for all the formulations.

Dissolution medium : 900 ml of phosphate buffer (pH 6.8) for 60 min.

Temperature : 37C 1C

Stirring speed : 100 rpm

Tablet taken : One tablet (drug content known) in each basket

Volume withdrawn : 10 ml every 2 minutes

Volume made up to : 10 ml

max : 261 nm

Beers range : 1-20 g/ml

Dilution factor : 10 ml

Dissolution test for Rifampicin dispersible formulations:



80/361


Volume made up to : 10 ml

max : 333 nm

Beers range : 1-10 g/ml

Dilution factor : 10 ml

Dissolution test for Isoniazid and Rifampicin combination formulation:

In vitro release studies were carried out using tablet dissolution test apparatus

USP XXIII dissolution apparatus type 1. The following procedure was employed

throughout the study to determine the in vitro dissolution rate for all the formulations.

The drug content in the formulation was estimated by the simultaneous estimation

method.

Dissolution medium : 900 ml of phosphate buffer (pH 6.8) containing

0.02%w/v ascorbic acid.

Temperature : 37C1

C

Stirring speed : 100 rpm

Tablet taken : One tablet (drug content known) in each basket



81/361


12. Curve Fitting Analysis:

The mechanism of drugs released from the matrix system was studied by fitting

the dissolution data in five different models.

i) Zero Order Equation

ii) First Order Equation

iii) Korsmeyer-Peppas Equation

iv) Higuchi Square Root Equation

v) Hixson Crowell Equation

13. Comparative In Vitro Drug Release Studies Between Formulations Developed

and Marketed Formulations:

Evaluations of formulations developed were subjected for comparative evaluation

of physicochemical parameters. In vitrodrug release of the promising formulation was

compared with marketed product of Isoniazid, Rifampicin and combination formulations

viz. conventional tablet preparations.

Details of Marketed Product:



82/361


3) Bicox-KID 50 (INH & Rifampicin combination Tablets)

Manufacturer- Overseas HC Pharma Ltd.

Mfg Date- May 2007

Expiry- April 2009

Batch No- AD4583 KL43

14. Scanning Electron Microscopy:126,127,128

SEM has been used to determine particle size distribution, surface topography,

texture and to examine the morphology of fractured or sectioned surfaces. The SEM is

most commonly used for generating three dimensional surface relief images derived from

secondary electrons. The examination of the surface of polymeric drug delivery systems

can provide important information about the porosity and microstructure of the device.

Instruments Used:

JEOL JSM-T330A Scanning Microscope

JEOL JFC-1100E Ion Sputter

LINK ANALYTICAL Electron Microscope Column

Mamiya Camera



83/361


2) Mounting:

The dried sample was attached to the brass sample holder or stub using an

adhesive substance.

3) Coating:

Thin coating of an electron dense metal (gold) was applied to the mounted sample

using the JOEL JFC-1100E Ion Sputter which is having a vacuum chamber. The chamber

was evacuated using a rotary pump and an inert carrier gas, argon was introduced to

produce partial vacuum of 10-2

mmHg. The argon atmosphere ionize by electrodes

located near gold metal foil, thereby heavy metal atoms were ejected from the foil,

covering the mounted sample with finely dispersed coating.

4) Imaging:

These samples were removed from the Ion Sputter and mounted on a sample

holder and placed in a LINK ANALYTICAL Electron microscope column and scanned

in a controlled raster pattern by an electron beam using JEOL JSM-T330A Scanning

Microscope. These electrons were collected with a detector which produced three

dimensional images of the sample surface on a TV screen attached to the microscope.



84/361

p

ratio of the integrated intensity of the sample to that of hydrocellulose, a crystalline

standard prepared from cellulose by treating with 2.5 N HCl at boiling temperature.

16. Microbiological Screening132-136

Anti-tubercular Activity:

Lawenstain-Jensens medium (L.J. medium) was used for the screening described

by Watt et alagainst human strain (H37Rv).

Preparation of media: its composition

Beaten egg (20 to 22 Henss egg, Depanding on size): 1000 ml

Mineral salt solution: 600 ml

Malachite green solution: 20 ml

Preparation of mineral salt solution:

Potassium dihydrogen Phosphate (Anhydron): 2.40 g

Magnesium Sulphate: 0.24 g

Magnesium Citrate: 0.60 g

Aspargine: 3.60 g

Glycerol: 12.0 ml

Chapter IV M

vikesh kumar

Documents