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FORMULATION AND EVALUATION OF MOUTH

DISSOLVE TABLETS OF SALBUTAMOL


SULPHATE

By
IMRAN AHMED
Reg. No. 04PU255

Dissertation Submitted to the


Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

In partial fulfillment
of the requirements for the degree of

MASTER OF PHARMACY
in
PHARMACEUTICS

Under the Guidance of


Mr.S.S.BUSHETTI
M.Pharm. (Ph.D.)

DEPARTMENT OF PHARMACEUTICS
LUQMAN COLLEGE OF PHARMACY,
GULBARGA-585 102

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APRIL 2006

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,


KARNATAKA, BANGALORE

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation/ thesis


entitled “FORMULATION AND EVALUATION OF
MOUTH DISSOLVE TABLETS OF SALBUTAMOL
SULPHATE” is a bonafide and genuine research work
carried out by me under the guidance of
Mr.S.S.BUSHETTI.

Date:
Place: GULBARGA IMRAN AHMED

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE

CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled

“FORMULATION AND EVALUATION OF MOUTH

DISSOLVE TABLETS OF SALBUTAMOL SULPHATE” is

a bonafide research work done by Mr.IMRAN AHMED

in partial fulfillment of the requirement for the degree of

MASTER OF PHARMACY in PHARMACEUTICS.

Date:
Place: GULBARGA S.S.BUSHETTI
M.Pharm. (Ph.D.)
Research Guide
Department of Pharmaceutics
Luqman College of Pharmacy,
Gulbarga

iii

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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE

ENDORSEMENT BY THE HOD, PRINCIPAL/


HEAD OF THE INSTITUTION

This is to certify that the dissertation entitled

“FORMULATION AND EVALUATION OF MOUTH DISSOLVE

TABLETS OF SALBUTAMOL SULPHATE” is a bonafide research

work done by Mr.IMRAN AHMED under the guidance of

Mr.S.S.BUSHETTI.

Date:
Place: GULBARGA Prof.Syed Sanaullah
Principal,
Luqman College of Pharmacy,
Gulbarga-585102

iv

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COPYRIGHT

DECLARATION BY THE CANDIDATE

I here by declare that the Rajiv Gandhi University of


Health Sciences, Karnataka shall have the rights to
preserve, use and disseminate this dissertation/ thesis in
print or electronic format for academic/ research purpose.

Date:
Place: GULBARGA IMRAN AHMED

© Rajiv Gandhi University of Health Sciences, Karnataka

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ACKNOWLEDGEMENT

I consider my self lucky to work under the guidance of


Mr.S.S.Bushetti, Assistant Professor, Department of Pharmaceutics,
Luqman College of Pharmacy, Gulbarga. His continuous guidance and
support have always propelled me to perform better. I am thankful to his
constant source of encouragement and support, which provide to impetus
and paved the way for the successful completion of this research work.

It is my privilege to express my heart felt thanks to Prof.Syed


Sanaullah, Principal, Dr.Syed Rehmatullah, Founder Secretary,
Dr.Mujeeb, Treasurer, Luqman College of Pharmacy, Gulbarga, and
Mr.Abdul Majeed, President, Vocational Education Society, Gulbarga,
for providing me all facilities and encouragement throughout the research
work.

A very special thanks to Mr.Purohit Sir, Mrs.Syeda Humera for


their constant support in analytical works.

I sincerely thank to Mr.M.A.Saleem, Co-guide, Dr.M.H.Dehghan,


Prof.Satyanandam Sade, Mr.K.Divakar, Mr.Najmuddin, Mr.Khaja
Pasha for their moral support, healthy criticism and valuable suggestions
regarding the work.

My sincere thanks to Mr.Adil Shareef, Mr.Khalid S.,


Mr.M.H.Hugar, Mr.Durga Rao, Mr.Md.Jaffar, Mr.Asghar Ali,
Mr.Omar Khan, Mr.Zia Sajid, Mr.Ashfaque Ahmed Mohsin, Mr.Aejaz,
Luqman College of Pharmacy, Gulbarga for their timely guidance in
enriching my knowledge and encouragement during the course of my
work.

I render my grateful respect and sincere thanks to my beloved


parents. I would like to extend my gratitude to Hazrath and my elder
brother Irfan Ahmed Mullan and Ashfaq Bhaijan without whom it could
not have been possible for me to complete this project work.

I express my special thanks to M/s.Micro Labs, Bangalore (Ilayas


Ahmed), Signet, Mumbai for providing gift samples of salbutamol sulphate
and super-disintegrants and Sipra Labs Pvt. Ltd., Hyderabad for their
help in getting the IR done.

I express my deep sense of thanks for the memorable valuable


company of Vafa-ul-Haque, Qayyum Shakir, Shafeeq (Vins).

vi

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I welcome this golden opportunity to express my heartfelt thanks to
my friends Arifullah, Abdullah, Altaf and Farhat Fatima who remained
as copious constant source of inspiration in hard times during the course.

It gives me immense pleasure to record my sincere thanks to my


senior colleagues and friends Rizwan Ahmed, Mouzam, Faizan Sayeed,
Jai Deo Pandey, Hafeez, Mohan V.K., Vinod Singh, Anantrao Kulkarni,
Md.Tahir, Md.Muqtadar Ahmed, Aleem, Md.Asif, Nagsesha Reddy, for
helping me in carrying out this work.

My sincere thanks to my juniors especially Mr.Sarim Imam,


Mr.Abhishek Bansal, Mr.Fazeel Ahmed, Mr.Narsimharaju,
Mr.Jagdeesh Shetkar, and Mr.Pampathi for their cooperation.

I am thankful to Mr.Narendra Kumar, Mr.Peer Pasha, Mr.Ismail,


Mr.Mashak other Non-teaching staff and Librarian Ms.Rubina Anjum &
Ms.Pratibha of Luqman College of Pharmacy, Gulbarga, for their co-
operation.

At the outset, I would like to express my sincere gratitude to all


those who have directly or indirectly helped me in making my project a
success.

And above all, words fail to express my feeling to my parents,


whose initiation, constant source of inspiration and encouragement
throughout this course.

Last but not the least, I would like to thank Fayaz Ahmed, Micro
Computers for making this thesis work in a reproducible manner.

Date:
Place: Gulbarga IMRAN AHMED

vii

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LIST OF ABBREVIATIONS USED

% w/v ............. Percentage weight / volume

SSG ................ Sodium starch glycolate

CP................... Crospovidone

CCS ................ Croscarmellose sodium

MCC............... Microcrystalline cellulose

Formulation Code:

S1 to S6............ Sublimation technique

DC1 to DC6 ..... Direct Compression technique

viii

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ABSTRACT

New era in an era of Novel Drug Delivery System Formulation research is


oriented towards increasing safety and efficacy of existing drug molecule through
novel concepts of drug delivery. Salbutamol sulphate is a selective 2 receptor
agonist widely used as bronchodilator. In the present research work an attempt
has been made to formulate and evaluate mouth dissolving tablets of salbutamol
sulphate. Mouth dissolving tablets of salbutamol sulphate were prepared using
sodium starch glycolate, croscarmellose sodium and cros-povidone as
superdisintegrants by direct compression and sublimation methods. The tablets
prepared were evaluated for various parameters like weight variations, hardness,
friability, in vitro dispersion time, drug-polymer interaction, drug content, water
absorption ratio and wetting time and in vitro drug release. The tablets prepared
by direct compression method possess a weight variation below ±7.5%, hardness
of 2.5 to 4.0 Kg/cm², percentage friability of 0.51 to 0.84, in vitro dispersion time
of 11 to 63 seconds, IR spectral analysis showed that there was no drug
interaction with formulation additives of the tablet, drug content uniformity was
in between 96.35 to 104.30%, water absorption ratio of 68.00 to 81.88%, wetting
time of 8 to 48 seconds, and in vitro drug release showed 91.46% to 100.60%
within 5 minutes. Similarly the tablets prepared by sublimation method possess a
weight variation below ±7.5%, hardness of 2.00 to 3 Kg/cm², in vitro dispersion
time of 4 to 39 seconds, IR spectral analysis showed that there was no drug
interaction with the formulation additives of the tablet, drug content uniformity
was in between 94.27 to 101.44%, water absorption ratio showed 67.56 to
77.98%, wetting time between 5 to 39 seconds and in vitro drug release of 91.46
to 100.60% within 4 minutes respectively.

ix

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TABLE OF CONTENTS

CHAPTER-1 INTRODUCTION ............................................................ 01-11


1.1 Desired Criteria for Mouth Dissolving Drug
Delivery System........................................................... 03
1.2 Salient Features of Mouth Dissolving Tablets .............. 03
1.3 Techniques for Preparing Mouth Dissolving Tablets .... 04
1.4 Patented Technologies for Mouth Dissolving
Tablets ......................................................................... 07

CHAPTER-2 OBJECTIVES .................................................................. 12-13


2.1 Need for the Study ....................................................... 12
2.2 Objectives of the Study ................................................ 13

CHAPTER-3 REVIEW OF LITERATURE .......................................... 14-34


3.1 Past work on Mouth Dissolving Tablets ....................... 14
3.2 Drug Profile ................................................................. 21
3.3 Polymer Profile............................................................ 27

CHAPTER-4 METHODOLOGY ........................................................... 35-48


4.1 Materials Used with their Source ................................. 35
4.2 Equipments .................................................................. 36
4.3 Standard Calibration Curve of Salbutamol Sulphate ..... 37
4.4 Method of Preparation of Mouth Dissolving Tablets .... 39
4.5 Evaluation of Tablets ................................................... 45

CHAPTER-5 RESULTS ......................................................................... 49-67

CHAPTER-6 DISCUSSION ................................................................... 68-72

CHAPTER-7 CONCLUSIONS............................................................... 73-74

CHAPTER-8 SUMMARY ...................................................................... 75-76

CHAPTER-9 BIBLIOGRAPHY............................................................. 77-82

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LIST OF TABLES

Sl. Page
Title
No. No.
1. List of Commercially Available Orodispersible Tablets 11
2. Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at 37
max 277nm
3. Formulation of Salbutamon Sulphate Mouth Dissolving Tablets 41
Prepared by Direct Compression Method (1-tablet)
4. Formulation of Salbutamon Sulphate Mouth Dissolving Tablets 42
Prepared by Direct Compression Method (50-tablets)
5. Formulation of Salbutamol Sulphate Mouth Tablet Prepared by 43
Sublimation Method (1-tablet)
6. Formulation of Salbutamol Sulphate Mouth Tablet Prepared by 44
Sublimation Method (50-tablets)
7. Weight Variation for Direct Compression Method 49
8. Weight Variation for Sublimation Method 51
9. Tablet Hardness for Direct Compression Method 53
10. Tablet Hardness for Sublimation Method 53
11. Percentage Friability for Direct Compression Method 54
12. Percentage Friability for Sublimation Method 54
13. In Vitro Dispersion Time for Direct Compression Method 55
14. In Vitro Dispersion Time for Sublimation Method 55
15. Drug Content for Direct Compression Method 64
16. Drug Content for Sublimation Method 64
17. Water Absorption Ratio and Wetting Time of Tablets Prepared by 65
Direct Compression Method
18. Water Absorption Ratio and Wetting Time of Tablets Prepared by 65
Sublimation Method
19. In vitro drug release of salbutamol sulphate by direct compression 66
method
20. In vitro drug release of salbutamol sulphate by Sublimation Method 67

xi

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LIST OF FIGURES

Sl. Page
Title
No. No.
1. Steps involved in the development of mouth dissolving tablets by 6
sublimation technique
2. Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at 38
max 277 nm
3. Development of pores in tablet after sublimation 40
4. Schematic representation of wetting time/ water absorption ratio 47
determination
5. Graphical representation of In Vitro Dispersion Time for Direct 56
Compression Method
6. Graphical representation of In Vitro Dispersion Time for 56
Sublimation Method
7. IR Spectra of Salbutamol Sulphate 57
8. IR Spectra of Formulation DC2 58
9. IR Spectra of Formulation DC4 59
10. IR Spectra of Formulation DC6 60
11. IR Spectra of Formulation S2 61
12. IR Spectra of Formulation S4 62
13. IR Spectra of Formulation S6 63
14. Graphical representation of drug released prepared by direct 66
compression method
15. Graphical representation of drug released prepared by sublimation 67
method

xii

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CHAPTER–1

INTRODUCTION

The oral route of administration still continue to be the most preferred

route due to its manifold advantages including ease of ingestion, pain avoidance,

versatility and most importantly patient compliance. The most popular dosage

form being tablets and capsules1. Even few of the drawbacks of these dosage

forms like swallowing1 and some drugs resist comparison in dense compacts,

owing to their amorphous nature or flocculant, low-density characteristics. Drugs

with poor wetting, slow dissolution properties, intermediate to large dosage,

optimum absorption in the gastrointestinal tract or any combination of these

features may be difficult or impossible to formulate and manufacture as a tablet

that will still provide adequate or full drug bioavailability.

Bitter tasting drugs, drugs with an objectionable odor, or drugs that are

sensitive to oxygen or atmospheric moisture may require encapsulation or

entrapment prior to compression.

The target population of these dosage forms are pediatric, geriatric,

bedridden, developmentally disabled and the patients with persistent nausea or

who are in traveling or who have little access to water2.

Even many patients find it difficult to swallow tablets and hard gelatin

capsules and thus do not comply with prescription, which results in high

incidence of non-compliance and ineffective therapy3.

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Recent advances in novel drug delivery systems (NDDS) aim to enhance

safety and efficacy of drug molecule by formulation and to achieve better patient

compliance. One such approach is ‘mouth dissolving tablets’4, which disintegrate

or dissolve in saliva and are swallowed without water as tablet disintegrate in

mouth, this could enhance the clinical effect of drug through pregastric absorption

from the mouth, pharynx, esophagus. This leads to an increase in the

bioavailability by avoiding first pass liver metabolism3.

Salbutamol sulphate is a 2 receptor agonist widely used as bronchodilator

to relieve acute as well as chronic attacks of asthma. Asthma is a complex genetic

disorder involving the interplay between various environmental and genetic

factors5. Salbutamol sulphate was selected as drug candidate as it is not available

in such a dosage form3.

Mouth dissolving is also called as orodispersible tablets, melt-in-mouth,

fast dissolving tablet, rapimelts, porous tablets, quick dissolving, etc.

Their growing importance was underlined recently when European

Pharmacopoeia adopted the term “Orodispersible Tablets” as a tablet that to be

placed in the mouth where it disperses rapidly before swallowing. It is one of the

fastest growing segment in the pharmaceutical market 6.

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1.1 DESIRED CRITERIA FOR MOUTH DISSOLVING DRUG

DELIVERY SYSTEM7,8:

The tablets should

i) Not require water to swallow, but is should dissolve or disintegrate

in the mouth in matter of seconds.

ii) Be compatible with taste masking.

iii) Be portable with taste masking.

iv) Have a pleasing mouth feel.

v) Leave minimal or no residue in the mouth after oral administration.

vi) Exhibit low sensitivity to environmental conditions as humidity

and temperature.

vii) Allow the manufacture of tablet using conventional processing and

packaging equipment at low cost.

1.2 SALIENT FEATURES OF MOUTH DISSOLVING TABLET9,10:

a) Ease of administration to patient who refuses to swallow tablets, such

as pediatric, geriatric and psychiatric patients.

b) No need of water to swallow the dosage form, which is highly

convenient feature for patients who are traveling and do not have

immediate access to water.

c) Rapid dissolution and absorption of drug, which will produce quick

onset of action.

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d) Some drugs are absorbed from the mouth, pharynx and esophagus as

the saliva passes down into the stomach, in such cases bioavailability

of drugs is increased.

e) Pregastric absorption can result in improved bioavailability and as a

result of reduced dosage, improve clinical performance through a

reduction of unwanted effects.

1.3 TECHNIQUES FOR PREPARING MOUTH DISSOLVING TABLETS:

Freeze Drying: 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 sometimes 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. Scherer RP patented Zydis technology by employing

freeze drying process for the preparation of mouth dissolving tablets on the basis

of patents issued to Gregory et al. Jaccard and Leyder also utilized lypholization

to prepared orodispersible tablets of various drugs.

Moulding: Tablets produced by moulding are solid dispersions. Physical form of

the drug in the tablets depends whether and to what extent it dissolves in the

molten carrier. The drug can exist as discrete particles or microparticles dispersed

in the matrix. It can dissolve totally in the molten carrier and the remaining

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particles stay undissolved and dispersed in the matrix. Disintegration time, drug

dissolution rate and mouth feel will depend on the type of dispersion or

dissolution. Moulded tablets disintegrate more rapidly and offer improved taste

because the dispersion matrix is, in general made from water soluble sugars.

Moulded tablets typically do not posses great mechanical strength. Erosion and

breakage of the moulded tablet often occur during handling and opening of blister

packs.

Sublimation: Because of low porosity, compressed tablets composed of highly

water-soluble excipients as tablet matrix material often do not dissolve rapidly in

water. Porous tablets that exhibit good mechanical strength and dissolved quickly

have been developed. Inert solid ingredients (e.g., urea, urethane, ammonium

carbonate, camphor, naphthalene) were added to other tablet excipient and the

blend was compressed into tablet. Removal of volatile material by sublimation

generated a porous structure. Compressed tablets containing mannitol and

camphor have been prepared by sublimation technique. The tablets dissolve

within 10-20 seconds and exhibit sufficient mechanical strength for practical use.

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Figure-1: Steps involved in the development of mouth dissolving tablets by
sublimation technique

Spray Drying: Spray drying can be used to prepare rapidly dissolving tablets.

This technique is based upon a particulate support matrix that is prepared by spray

drying an aqueous composition containing support matrix and other components

to form a highly porous and fine powder. This is then mixed with active

ingredient and compressed into tablet. Allen and Wang have employed spray

drying technique to prepare orodispersible tablets.

Mass Extrusion: This technology involves softening the active blend using the

solvent mixture of water soluble polyethylene glycol, using methanol and

expulsion of softened mass through the extruder or syringe to get a cylinder of the

product into even segments using heated blade to form tablets. The dried cylinder

can also be used to coat granules of bitter tasting drugs and thereby masking their

bitter taste.

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Direct Compression: It is the easiest way to manufacture tablets. Conventional

equipment, commonly available excipients and a limited number of processing

steps are involved in direct compression. Also high doses can accommodated and

final weight of tablet can easily exceed that of other production method. Directly

compressed tablet’s disintegration and solubilization depends on single or

combined action of disintegrants, water-soluble excipients and effervescent agent.

Disintegrant efficacy is strongly affected by tablet size and hardness. Large and

hard tablets have disintegration time more than that usually required. As

consequences, products with optimal disintegration properties often have medium

to small size and/ or high friability and low hardness. Breakage of tablet edges

during handling and tablet rupture during the opening of blister alveolus, all

results from insufficient physical resistance.

1.4 PATENTED TECHNOLOGIES FOR MOUTH DISSOLVING TABLETS:

Zydis Technology11: 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 during handling, polymers such as

gelatin, dextran or alginates are incorporated. These form a glossy amorphous

structure, which imparts strength. To obtain crystallinity, elegance and hardness,

saccharides such as mannitol or sorbitol are incorporated. Water is used in the

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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 the shrinkage of zydis unit during freeze drying process or long-term

storage. Zydis products are packed in blister packs to protect the formulation

from moisture in the environment.

Shearform Technology: The shearform technology is based on preparation of

floss that is also known as ‘shearform matrix’, which is produced by subjecting a

feedstock containing a sugar carrier by flash heat processing. In this process, the

sugar is simultaneously subjected to centrifugal force and to a temperature

gradient, which raises the temperature of the mass to create an internal, flow

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

mass exists through the spinning head that flings the floss. The floss so produced

is amorphous in nature so it is further chopped and recrystallized by various

techniques to provide uniform flow properties and thus facilitate blending. The

recrystalized matrix is then blended with other tablet excipient and an active

ingredient. The resulting mixture is compressed into tablet. The active ingredient

and other excipient can be blended with floss before carrying out recrystallization.

The shearform floss, when blended with the coated or uncoated microspheres is

compressed into Flashdose or EZ chew tablets on standard tableting equipment.

Ceform Technology: In Ceform technology microspheres containing active drug

ingredient are prepared. The essence of ceform microsphere manufacturing

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process involves placing a dry powder, containing substantially pure drug

material or a special blend of drug materials plus other pharmaceutical

compounds, and excipients into a precision engineered 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 liquifies the drug blend to form a

sphere without adversely affecting drug stability. The microspheres are then

blended and/ or compressed into the pre-selected oral delivery dosage format. The

ability to simultaneously process both drug and excipient 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 microspheres can be incorporated into a wide range

of fast dissolving tablets such as Flashdose, EZ chew, Spoon Dose, as well as

conventional tablets.

Durasolv Technology: Durasolv is the patented technology of CIMA labs. The

tablets made by this technology consist of a drug, fillers and a lubricant. Tablets

are prepared by using conventional tableting equipment and have good rigidity.

These can be packed into conventional packaging system like blisters. Durasolv

is an appropriate technology for products requiring low amounts of active

ingredients.

Orasolv Technology: CIMA labs have developed Orasolv Technology. In this

system active medicament is taste masked and also contains effervescent agent.

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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 produced are soft and friable

and packaged in specially designed pick and place system.

Wowtab Technology: Wowtab Technology is patented by Yamanouchi

Pharmaceutical Company WOW means “without water”. In this process,

combination of low mouldability saccharides and high mouldability saccharides is

used to obtain a rapidly melting strong tablet. The active ingredient is mixed with

a low mouldability saccharide and granulated with a high mouldability saccharide

and compressed into tablet.

Flashtab Technology: Prographarm laboratories have patented the Flashtab

technology. Tablets prepared by this system consist of an active ingredient in the

form of microcrystals. Drug microgranules may be prepared using the

conventional technique like coacervation, microencapsulation, and extrusion-

spheronization. All these processes utilized conventional tableting technology.

Nowadays orodispersible tablets are gaining more and more importance in

the market. Currently, these tablets are available in the market for many diseases;

more is concentrated on analgesics and anti-pyretics. Research is in progress for

anti-hypertensives, anti-emetics and anti-asthmatics. The list of commercially

available mouth dissolving tablets is shown in table-1.

10

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Table-1: List of Commercially Available Orodispersible Tablets11

Trade Name Active Drug Manufacturer


Feldene Fast Piroxicam Pfizer Inc., USA
Melt
Calritin Redi Loratidine Schering Plugh Corp, USA
Tab
Maxalt MLT Rizatriptan Merck & Co. USA
Zyprexia Olanzapine Eli Lilly, Indianapolis, USA
Pepcid RPD Famotidine Merck & Co., NJ, USA
Zofran ODT Ondansetron Glaxo Wellcome, Middlesex, UK
Zoming-ZMT Zolmitriptan AstraZeneca, Wilmington, USA
Zelpar TM Selegilline Amarin Corp., London, UK
Tempra Quiclets Acetaminophen Bristol Myers Squibb, NY, USA
Febrectol Paracetamol Prographarm, Chateauneuf, France
Nimulid MDT Nimesulide Panacea Biotech, New Delhi, India
Torrox MT Rofecoxib Torrent Pharmaceuticals, Ahmedabad,
India
Olanex Instab Olanzapine Ranbaxy Labs Ltd., New Delhi, India
Romilast Montelukast Ranbaxy Labs Ltd., New Delhi, India
Benadryl Diphenhydramine Warner Lambert, USA
Fastmelt and
pseudoephedrine

11

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CHAPTER–2

OBJECTIVE

2.1 NEED FOR THE STUDY:

The concept of mouth dissolving drug delivery system emerged from the

desire to provide patient with more conventional means of taking their

medication. It is difficulty for many patients to swallow tablets and hard gelatin

capsules. Hence, they do not comply with prescription, which results in high

incidence of non-compliance and ineffective therapy7.

In some cases such as motion sickness, sudden episodes of allergic attacks

or coughing and unavailability of water, swallowing conventional tablets may be

difficult8.

Such problems can be resolved by means of mouth dissolving tablets

when put on tongue these tablets disintegrate and dissolve rapidly in saliva

without need of drinking water. The faster the drug disintegrate in to solution, the

quicker the absorption and onset of clinical effect. Some drugs are absorbed from

the mouth, pharynx and esophagus as a saliva passes down into the stomach12.

In such cases, bioavailability of drug is significantly greater than those

observed from conventional tablets dosage form13.

Hence, in the present study an attempt will be made to formulate mouth

dissolving tablets of salbutamol sulphate (a direct-acting sympathomimetic with

12

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predominantly -adrenergic activity and a selective action on 2 receptor (2

agonist), used as bronchodilators in the management of reversible obstruction as

in asthma, with a view to develop a convenient means of administration to those

patients suffering from difficulties in swallowing, nausea and motion sickness14.

2.2 OBJECTIVES OF THE STUDY:

1. Preparation of mouth dissolving tablets of salbutamol sulphate by

direct compression using different concentration of superdisintegrants

like cross-linked carboxy methyl cellulose (AC-di-sol), sodium starch

glycolate (Explotab) and crospovidone (polyplasdone XL).

2. Mouth dissolving tablets of salbutamol sulphate were also prepared by

sublimation method using camphor as subliming agent and as and

using croscarmellose sodium (Ac-di-sol), sodium starch glycolate

(Explotab) and crosprovidone (polyplasdone XL) as

superdisintegrants.

3. Mouth dissolving tablets of salbutamol sulphate were evaluated for

hardness, friability, weight variation, disintegration time, drug content,

water absorption ratio, water absorption time, drug-excipient

interaction studies (IR spectroscopy).

4. Study in vitro dissolution of salbutamol sulphate from the formulated

mouth dissolving tablets.

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CHAPTER–3

REVIEW OF LITERATURE

3.1 PAST WORK ON MOUTH DISSOLVING TABLETS:

Avinash RM, Kusum Devi V, Asha AN15 have formulated mouth

dissolving tablets of domperidone by using a meltable binder (PEG-4000), a

diluent (mannitol) and a component which sublimes readily (camphor/

ammonium bicarbonate).

Shenoy V, Agarwal S, Pandey S16 have prepared rapidly disintegrating

tablets of diclofenac sodium by direct compression method using super-

disintegrants such as cross-linked carboxy methyl cellulose, sodium starch

glycolate and cross-linked povidone in varying concentrations.

Mahajan HS, Kuchekar BS, Badhan AC17 have prepared mouth dissolving

tablets of sumatriptan succinate by direct compression method using disintegrants

such as sodium starch glycolate, carboxy methyl cellulose sodium and treated

agar.

Chowdary KPR, Rao DS18 have prepared dispersible tablet formulations

of three poorly soluble drugs viz., sulfamethoxazole, piroxicam and

oxyphenbutazone were formulated using potato starch or microcrystalline

cellulose as disintegrants.

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Ito A, Sugihara M19 have prepared rapidly disintegrating oral tablets for

elderly patients with impaired swallowing by using agar as base.

Kuchekar BS, Badhan AC, Mahajan HS3 have formulated mouth

dissolving tablets of salbutamol sulphate by factorial design technique. Tablets

were prepared by direct compression method using super-disintegrants such as

sodium starch glycolate, cross-carmellose sodium and treated agar along with

microcrystalline cellulose as diluent.

Kaushik D, Dureja H, Saini TR20 have formulated mouth dissolving

tablets of olanzapine by using sodium bicarbonate and citric acid as effervescent

agents, which have the advantage of slight bitter taste masking effect.

Yunxia Bi et al21 have formulated tablets, which rapidly disintegrate in the

oral cavity using microcrystalline cellulose and low substituted hydroxypropyl

cellulose as disintegrants and ethanzamide and ascorbic acid as poorly and easily

water-soluble model drugs respectively.

Sunanda H et al22 have prepared rapidly disintegranting tablets using

microcrystalline cellulose as diluents and cross-linked sodium carboxy methyl

cellulose (AC-Di-Sol) erythritol are selected as response variables, tablet-porosity

and parameters representing the characteristics of formulations were selected as

controlling factors and the relation was determined by the polynomial regression

method.

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Simone Schiermeier et al23 have formulated fast dispersible tablets which

disintegrated either rapidly in water to form a stabilized suspension or disperse

instantaneously in the mouth to be swallowed without the aid of water. They

employed a rotatable central composite design to predict the effects of the

quantitative factors, mannitol and cross-povidone as well as compression force on

the characteristics of the tablet.

Hisakadsu Sunanda et al24 have developed rapidly disintegrating tablets

using both direct compression and wet compression methods. Tablet properties

such as porosity, tensile strength, wetting time and disintegrating time were

evaluated and the formulation and disintegration mechanisms of the tablets were

evaluated.

Akihiko Ito et al25 have developed rapidly disintegrating tablets for elderly

patients with impaired swallowing using agar powders and treated agar powders.

Ishikawa T et al26 have prepared tablets which can rapidly disintegrate in

saliva using taste-masked granules of drugs with bitter taste (pirenzepine HCl or

oxybutynin HCl). The taste masked granules were prepared using Eudragit-E100

by extrusion method.

Yoshiteru Watanabe et al27 have formulated rapidly disintegrating tablets

comprising of crystalline cellulose and low-substituted hydroxy propyl cellulose

(L-HPC).

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Chowdary KPR and Rama Rao N28 have carried out formulation and

evaluation of piroxicam tablets with piroicam pregelatinized starch dispersions.

Dispersions of piroxicam in pregelatinized starch were prepared in different drug

and carrier ratios and were evaluated by X-ray diffraction, differential thermal

analysis and differential scanning calorimetry studies. They claimed that all the

tablets formulated with piroxicam-pregelatinized starch physical mixtures,

dispersions were found to contain piroxicam within 100±5% of the labelled claim.

Thus, fast disintegrating tablets giving rapid dissolution of the drug could be

formulated employing piroxicam pregelatinized starch dispersions by

conventional wet granulation method.

Nayak SM and Gopal Kumar P29 have prepared fast dissolving tablets of

promethazine theoclate using effervescent melt, superdisintegrant addition and

melt technologies.

Chandrasekhara Rao G et al30 have prepared dispersible tablets of

nimesulide using primojel as dispersing agent with starch, lactose and dicalcium

phosphate as diluents.

Manvi FV et al31 have formulated dispersible tablets of flurbiprofen by

employing different disintegrants, such as pregelatinized starch (PGS),

microcrystalline cellulose (MCC) and sodium starch glycolate alone and in

different combinations containing different concentrations of disintegrants.

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Nazma S et al32 have formulated dispersible sparfloxacin tablets by direct

compression technique and wet granulation technique using super disintegrants

such as sodium starch glycolate.

Gupta GD and Gaud RS33 have formulated dispersible tablets of

nimesulide using natural substances as disintegrants such as plantago ovata seed

husk, cassia tora (sickle senna) and cassia nodosa in different concentrations.

Mishra DN et al2 have prepared rapidly disintegrating oral tablets of

valdecoxib using various superdisintegrants following direct compression

technique.

Chaudhari PD et al4 have formulated fast dissolving tablets of famotidine

using different superdisintegrants (AC-di-sol and polyplasdone) with varying

concentrations and the bitter taste of famotidine was masked using drug: Eudragit

E100 in different ratios.

Mahajan HS et al34 have prepared rapidly disintegrating tablets of

piroxicam using different super disintegrants such as sodium starch glycolate

(SSG), Carmellose, low substituted propyl cellulose and microcrystaline cellulose

(Avicel pH –102) was used as diluent.

Dandagi PM et al35 have prepared taste masked ofloxacin mouth

disintegrating tablets using Eudragit E100 as taste masking agent along with

Avicel pH 102 and ethanol (granulating fluid).

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Kaushik D et al36 have prepared melt-in-mouth tablets by sublimation

technique. Tablets were prepared by direct compression using directly

compressible mannitol and ammonium bicarbonate as volatile salt. The

sublimation of ammonium bicarbonate from compressed tablets at appropriate

conditions resulted in tablets with decreased weight and rapid disintegration.

Pavankumar GV et al37 prepared buccal films of salbutamol sulphate using

three different polymers in various proportions and combinations and concluded

that the polymers and their combination influenced the film properties as well as

release characteristics.

Bhalla HL et al38 developed two formulations of controlled release

hydrophilic matrix tablets of salbutamol sulphate based on HPMC and its

combination with gum have reported. Formulations showing an appropriate in

vitro release pattern were evaluated for in vivo activity and haveexhibited a

sustained bronchodilatory effect.

Kale P, Warrier HC et al39 studied the stability and skin permeation of

salbutamol base from adhesive matrix transdermal patches containing

antioxidants and skin permeation enhancers was studied. Skin permeation was

enhanced with increase in salbutamol content and oleic acid content in the

patches.

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Garg R et al40 studied third derivative amplitude at 233.8 and 303 nm,

selected for the assay of salbutamol and ethopyride in combination respectively.

The proposed method is successfully applied to the combination of these drugs in

laboratory mixture and in tablet dosage form.

Kotaro Lida et al41 reported the in vitro inhalation properties increased

with the rotor rotation rate using this surface processing system would thus be

valuable for increasing the inhalation properties of dry powder inhalation with

lactose carrier particles.

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3.2 DRUG PROFILE42-46:

Chemical Names:

a) 1,3-benzene dimethanol {[(1,1-dimethyl ethyl) amino] methyl}-4-hydroxy

sulphate (2:1) salt.

b) M-xylene-- diol  [(tert butyl amino) methyl] 4-hydroxy.

c)  [(tert butylamino) methyl]-4 hydroxy m-xylene , -diol.

d)  (tert butylamino)-1-(4-hydroxy 3 hydroxy methyl phenyl) ethanol.

e) 4-hydroxy-3-hydroxy-methyl [(tert butylamino) methyl] benzyl alcohol.

f) 1-(4-hydroxy-3 hydroxy methyl phynyl)-2 (tert butylamino) ethanol.

Structural Formula:
OH

OH CH CH2NHC(CH3)3, ½H2SO4

HOH2C

Molecular weight: 288.35

Molecular formula: C13H21NO3, ½H2SO4

Description: White or almost white powder, odorless and slightly bitter in taste.

Standards: Salbutamol sulphate IP (1985) contains not less than 98% and not

more than 101% of C13H21NO3, ½ H2SO4 calculated with reference to the dried

substance.

Solubility: Soluble one in four parts of water. Slightly soluble in ethanol 96%,

chloroform and ether.

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Storage: It should be protected from light.

Melting point: 150ºC.

Synonym: Albuterol sulphate.

Category: This drug is a selectively acting beta-2-receptor stimulant essentially

devoid of  and  activity. It is a direct acting, adrenergic, sympathomimetic

bronchodilator.

Pharmacokinetic Properties:

Absorption: Rapidly absorbed after oral administration and after inhalation; most

of the inhaled dose is swallowed and more enters the lungs with positive

intermittent breathing than by aerosol.

Distribution: After an oral dose of 4-8 mg peak plasma concentration of about 23

ng/ml for unchanged drug and 50-100 ng/ml for drug plus metabolite are attained

in 2.5-3 hours. After an inhaled dose of 80 g, peak plasma concentrations of

about 0.2 ng/ml for unchanged drug and about 1 ng/ ml for drug plus metabolite

are attained in about 3 hours; 2 hours after an intravenous dose of 200 g a

plasma concentration of about 1 ng/ml is obtained for the unchanged drug and

about 2 ng/ml for drug plus metabolite.

Metabolism: The drug is metabolized by the first pass metabolism, the reactions

and metabolites involved are not yet identified.

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Elimination: About 75-95% of an oral dose is excreted in urine and about 4% in

the faeces in 3 days, after administration as an aerosol, up to 97% is excreted in

the urine and about 11% in the faeces, after IV dose 80% is excreted in the urine

and 4% in faeces, about 20% of an inhaled dose is lost in the air and in the oral

adapter following oral administration or inhalation. About 50-60% of the urinary

excreted material is metabolized but after intravenous administration only about

27% is excreted in metabolized form. The inactive metabolite is sulphate

conjugate and about 25% of the administered dose is metabolized to the 4-0-

sulphate ester.

Half-Life: Plasma half-life is 2-7 hours. In general, the shorter half-life is seen

with intravenous administration, the intermediate values after oral administration

and the longer values after aerosol inhalation. It has been suggested that the

slightly extended half-life following inhalation may be due to slow removal of

active drug from the lungs. Salbutamol does not cross the blood brain barrier to a

significant extent, but it crosses the placental barrier.

Pharmacology:

Salbutamol exerts a relatively selective action on the 2 adrenergic

receptors of the bronchial and vascular smooth muscles. It is administered either

by inhalation or orally for the symptomatic relief of bronchospasm associated

with chronic or acute asthma, bronchitis or other obstructive pulmonary diseases.

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Action:

Salbutamol is a directly acting sympathomimetic amine with a more

selective action than isoprenaline. Albuterol is long lasting and less likely to

cause cardiovascular side effects than other adrenergic bronchodilators. It may be

a preferred adrenergic agonist because it produce minimal arrhythmia and fall in

the partial pressure of peripheral arteriolar oxygen. It causes slight fall in blood

pressure rather than an increase.

Uses:

It is used in the treatment of asthma, chronic bronchitis, emphysema and

other bronchopulmonary disorders involving bronchospasm. The drug is also

used to arrest premature labour and in ocular hypertension. It is effective when

applied topically but it often causes severe hyperenia. In congestive heart disease,

it is used for low output states. The drug improves cardiac output by reducing left

ventricular after load but has little effect on ventricular filling pressure.

Dose:

Salbutamol is used as the base in aerosol inhalers and as the sulphate salt

in other dosage forms. A dose equivalent to 2 to 4 mg of salbutamol, 3 or 4 times

per day is prescribed for adults, while for children of 2-6 years, a dose of 1-2 mg,

3 or 4 times and 2 mg for older children is prescribed.

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Salbutamol is administered as an aerosol inhalation in doses of up to 200

micrograms 3 or 4 times a day. The usual dose for children is on inhalation of

100 micrograms 2-4 times daily.

Salbutamol sulphate is used as a respiratory solution containing the

equivalent of 0.5% salbutamol.

A solution for injection containing the equivalent of 50 or 500 micrograms

or one milligram of salbutamol per milliliter is used in bronchospasm. The usual

dose by subcutaneous or intramuscular injection is equivalent of 8 micrograms of

salbutamol per kilogram body weight every 4 hours and slow intravenous

injection, 4 microgram per Kg body weight, repeated as necessary. A solution of

10 micrograms of salbutamol per milliliter for intravenous infusion, in the status

of asthmatics-usual dose is 3-20 micrograms per minute as initial dose in

premature labour of the third trimester at 10 minute intervals until the contractions

are reduced.

Note: 1.2 mg of salbutamol sulphate is approximately equivalent to 1 mg of


salbutamol.

Adverse Effects:

Salbutamol may give rise to tremor of skeletal muscle (fine finger tremor),

palpitations and muscle cramps. Slight tachycardia, tenseness, headaches and

peripheral vasodilation after longer doses. The injection may give rise to nausea,

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vomiting and headache. This can be treated by using a cardioselective -

adrenoreceptor blocking agent.

Precaution and Contraindications:

It is contraindicated in patients with hypertension, myocardial

insufficiency and hyperthyroidism and in patients with diabetes mellitus, serious

cardiovascular disorders. The excessive use of spray may lead to fatal results. It

should not be administered with non-selective beta-adrenoreceptor blocking drugs

such as propranolol or oxprenolol.

In addition, parenteral salbutamol should not be administered during the

first and second trimester of pregnancy and should not be used in premature

labour associated with toxaemia of pregnancy or antepartum hemorrhage.

Tolerance:

In healthy subjects specific airway conductance was progressively

decreased when salbutamol up to 400 g 4 times daily was inhaled over a period

of 405 weeks. Hydrocortisone 200 mg IV or aminophylline will restored the

response.

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3.3 POLYMER PROFILE47:

Croscarmellose Sodium:

Synonyms: Ac-Di-Sol, cross-linked carboxymethylcelluolse sodium, modified

cellulose gum, Nymcel ZSX, Primellose, Solutab.

Functional Category: Tablet and Capsule disintegrant.

Applications: As a disintegrant for tablets (wet granulation and direct

compression), capsules and granules in 2-5 % concentration.

Description: Odorless, white-colored powder.

Solubility: Insoluble in water, although it swells to 4 to 8 times its original

volume on contact with water.

Stability: It is a stable though hygroscopic material.

Storage conditions: It should be stored in a well-closed container in a cool, dry,

place.

Incompatibilities: Efficacy may be slightly reduced in formulations containing

hygroscopic excipients like sorbitol.

Safety: It is generally regarded as a nontoxic and nonirritant material. However,

oral ingestion of large quantities may have a laxative effect.

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Crospovidone

Synonyms: Cross-linked povidone, Polyplasdone XL, PVPP, polyvinylpoly-

pyrrolidone.

Functional Category: Tablet disintegrant.

Applications: Is a water insoluble tablet disintegrant used at 2-5 % concentration

in tablets prepared by direct compression or wet & dry granulation method.

Description: White to creamy-white, finely divided, free-flowing, practically

tasteless, odorless or nearly odorless, hygroscopic powder.

Solubility: Practically insoluble in water and most organic solvents.

Stability: Crospovidone is stable.

Storage conditions: Since it is hygroscopic it should be stored in an airtight

container in a cool, dry, place.

Incompatibilities: When exposed to a high water level it may form molecular

adducts with some materials.

Safety: It is generally regarded as a nontoxic and nonirritant material.

Sodium Starch Glycolate:

Synonyms: Carboxymethyl starch, Explotab, Primogel.

Functional Category: Tablet and Capsule disintegrant.

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Applications: As a disintegrant in tablet (wet granulation and direct compression)

and capsules formulations in 2-8 % concentration.

Description: White to off-white, odorless, tasteless, free-flowing powder.

Solubility: Practically insoluble in water, sparingly soluble in ethanol (95 %). In

water it swells upto 300 times its volume.

Stability: It is a stable material.

Storage conditions: It should be stored in a well-closed container to protect from

wide variations in humidity and temperature that may cause cracking.

Incompatibilities: Incompatible with Ascorbic acid.

Safety: It is generally regarded as a nontoxic and nonirritant material. However,

oral ingestion of large quantities may be harmful.

Microcrystalline Cellulose:

Synonyms: Avicel, cellulose gel, crystalline cellulose, E460, Emocel, Fibrocel,

Tabulose, Vivacel.

Functional Category: Tablet and Capsule diluent, suspending agent, adsorbent,

tablet disintegrant.

Applications: As a diluent in tablets (wet granulation and direct compression)

and capsule formulation. In addition to its use as a diluent, it also has some

lubricant and disintegrant property.

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Description: White-colored, odorless, tasteless crystalline powder composed of

porous particles. Available in different particle size grades which have different

properties and applications.

Solubility: Slightly soluble in 5 % w/v NaOH solution, practically insoluble in

water, dilute acids and most organic solvents.

Stability: It is a stable, though hygroscopic material.

Storage conditions: The bulk material should be stored in a well-closed container

in a cool, dry, place.

Incompatibilities: Incompatible with strong oxidizing agents.

Safety: It is generally regarded as a nontoxic and nonirritant material.

Lactose:

Synonyms: Fast-Flo, Microlose, milk sugar, Pharmatose, Tablettose.

Functional Category: Tablet and Capsule diluent.

Applications: As filler or diluent in tablets (wet granulation and direct

compression) and capsules, in lyophilized products and infant fed formulas.

Description: White to off-white crystalline particles or powder, odorless and

slightly sweet-tasting.

Solubility: Freely soluble in water, practically insoluble in chloroform, ethanol

and ether.

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Stability: Under humid conditions (80 % Rh and above) mold growth may occur.

Storage conditions: Lactose should be stored in a well-closed container in a cool

and dry place.

Incompatibilities: A Maillard-type condensation reaction is likely to occur

between lactose and compounds with a primary amine group to form brown-

colored products.

Safety: Adverse reactions to lactose is largely attributed to lactose intolerance,

which occurs in persons with a deficiency of the intestinal enzyme lactase.

Mannitol:

Synonyms: Cordycepic acid: E421; 1,2,3,4,5,6-hexanehol; manita; mauna sugar;

mannite; pearlitol.

Functional Category: Sweetening agent; tablet and capsule diluent; tonicity

agent; vehicle (bulking agent) for hyophilized preparations.

Applications in Pharmaceutical Formulation or Technology:

Mannitol is widely used in pharmaceutical formulations and food

products. In pharmaceutical preparations, it is primarily used as a diluent (10-

90% w/w) in tablet formulations, where it is of particular value since it is not

hygroscopic and may thus be used with moisture sensitive active ingredients.

Solubility: Soluble in alkalis, ethanol (95%), 1 in 83, ether practically insoluble,

glycerine1 in 18, propan-2-01 1 in 100; water 1 in 5.5.

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Stability: Mannitol is stable in the dry state.

Storage Conditions: The bulk material should be stored in a well closed

container in a cool, dry place.

Incompatibilities: None reported in the dry state.

Safety: Mannitol is a naturally occurring sugar alcohol found in animals and

plants. It is present in small quantities in almost all vegetables. Only small

amounts are absorbed from the gastrointestinal tract following oral consumption.

When consumed orally in large quantities laxative effects may occur. The

product label should bear the statement ‘excessive consumption may have a

laxative effect.

Camphor48:

C10H16O = 152.24

Natural camphor or producted synthetically.

Melting point between 174 and 179ºC  D , + 41º to +43º (natural, 10% w/v in
2D

ethanol, synthetic, optically inactive).

Magnesium Stearate:

Synonyms: HyQual, magnesium octadecanoate, stearic acid, magnesium salt.

Functional Category: Tablet and capsule lubricant.

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Applications: It is primarily used as a lubricant in capsule and tablet manufacture

at concentrations between 0.25-5.0 %.

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.

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

slightly soluble in benzene and warm ethanol (95 %).

Stability: Magnesium stearate is stable.

Storage conditions: It should be stored in a well-closed container in a cool, dry,

place.

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

strong oxidizing materials.

Safety: It is generally regarded as being nontoxic following oral administration.

However, oral consumption of large quantities may result in some laxative effect

or mucosal irritation.

Talc:

Synonyms: Magsil Osmanthus, Magsil Star, Purtalc, steatite

Functional Category: Glidant, tablet and capsule lubricant, anti-cracking agent.

Applications: It is used as a lubricant in solid dosage forms (1-10 %), in topical

preparations as dusting powder (90-99 %).

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Description: It is a very fine, white to grayish-white colored, odorless,

impalpable, unctuous powder. It adheres to the skin, is soft to touch, and free from

grittiness.

Solubility: Practically insoluble in dilute acids and alkalies, organic solvents, and

water.

Stability: Talc is a stable material.

Storage conditions: It should be stored in a well-closed container in a cool, dry,

place.

Incompatibilities: Incompatible with quaternary ammonium compounds.

Safety: Following oral ingestion talc is not absorbed systemically and may thus

be regarded as an essentially nontoxic material. Intranasal or IV abuse of products

containing talc can cause granulomas in body tissues, particularly the lungs.

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CHAPTER–4

METHODOLOGY

4.1 MATERIALS USED WITH THEIR SOURCE:

Sl.
Material Batch No. Property Source
No.

1. Salbutamol sulphate SSI0704023 Pure Drug Micro Labs,


Bangalore

2. Croscarmellose T506C Disintegrant Signet, Mumbai


sodium

3. Crospovidone 94632736WO Disintegrant Signet, Mumbai

4. Sodium starch E0630 Disintegrant Signet, Mumbai


glycolate

5. Lactose (DC) ES 5R 7226 Diluent Eros Pharma,


Bangalore

6. Microcrystalline -- Diluent Sd Fine Chemi Ltd.


cellulose

7. Mannitol G04Y/0404/ Diluent Loba Chemie


220/13

8. Camphor V1804041 Sublimating Sd Fine Chem Ltd.,


agent

9. Talc J032/1003/ Glidant Loba Chemie


1810/02

10. Magnesium stearate M-5632 Lubricant Sd Fine Chem Ltd.,

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4.2 EQUIPMENT:

Sl.
Equipment Model Make/Model
No.

1. Tablet compression machine CMSH/ Cadmach Single Punch


400/ 92 compression machine

2. Hardness Tester OSSCO Monsanto Hardness Tester

3. Friability Test Apparatus 020334 Veego Digital

4. Tablet Dissolution Test 220307 Electrolab USP (XXIII),


Apparatus Bangalore

5. UV Visible Spectrophotometer 1700 Shimadzu 1700, Japan

6. Oven Rotek 97070 Tempo Instruments &


Equipment

7. Balance BT 220H Shimadzu Digital Balance

8. pH meter 5291679 Hanna Instruments, Italy

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4.3 STANDARD CALIBRATION CURVE OF SALBUTAMOL

SULPHATE:

Solutions ranging from 5 to 25 g/ml were prepared using phosphate

buffer (pH 6.8); separately, absorbance was measured for each solution at max of

277 nm using Shimadzu UV/ visible 1700 spectrophotometer, graph was plotted

for absorbance versus concentration of salbutamol sulphate.

Table-2: Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at


 max 277nm

Concentration
Sl. No. Absorbance
(mcg/ml)
1. 00 0.00
2. 05 0.041
3. 10 0.070
4. 15 0.105
5. 20 0.138
6. 25 0.170

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Figure-2: Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at
 max 277 nm

0.18

0.16

0.14

0.12
Absorbance

0.1

0.08

0.06

0.04

0.02

0
0 5 10 15 20 25 30
Concentration (mcg/ ml)

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METHODS OF PREPARATION OF MOUTH DISSOLVING TABLETS

4.4 PREPARATION OF MOUTH DISSOLVING TABLETS BY

DIRECT COMPRESSION TECHNIQUE3:

Mouth dissolving tablets of salbutamol sulphate were prepared by direct

compression method according to the formula given in table-4.

All the ingredients were passed through 60 mesh sieve separately. The

drug and microcrystalline cellulose was mixed by small portion of both each time

and blending it to get a uniform mixture kept asid. Then the ingredients were

weighed and mixed in geometrical order and tablets were compressed at 7 mm

sizes flat round punch to get tablet using Cadmach Compression Machine.

PREPARATION OF MOUTH DISSOLVING TABLETS BY

SUBLIMATION TECHNIQUE36:

Mouth dissolving tablets of salbutamol sulphate were prepared by

sublimation method according to the formula given in table-6.

The ingredients after sifting thoroughly mixed for 10 minutes. Then

magnesium stearate was sifted through sieve No. 44 and added to blend and

thoroughly mixed. The tablets were compressed on 7 mm flat round punch on by

using cadmach compression machine. The compressed tablets were then

subjected to sublimation at 60ºC for 6 hours.

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(a) Before Sublimation

(b) After Sublimation

Figure-3: Development of pores in tablet after sublimation

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Table-3: Formulation of Salbutamon Sulphate Mouth Dissolving Tablets
Prepared by Direct Compression Method (1-tablet)

Sl.
Ingredients DC1 DC2 DC3 DC4 DC5 DC6
No.

1. Salbutamol 2.00 2.00 2.00 2.00 2.00 2.00


sulphate (mg)

2. Lactose (mg) (DC) 79.00 78.00 76.50 74.50 78.50 76.50

3. Croscarmillose 1.50 2.50 -- -- -- --


sodium (AC-di-
Sol) (%)

4. Sodium strach -- -- 4.00 6.00 -- --


glycolate
(Explotab) (%)

5. Crospovidone -- -- -- -- 2.00 4.00


(polyplasdone)
(%)

6. Microcrystalline 20.00 20.00 20.00 20.00 20.00 20.00


cellulose (mg)

7. Magnesium 0.50 0.50 0.50 0.50 0.50 0.50


stearate (mg)

8. Talc (mg) 5.00 5.00 5.00 5.00 5.00 5.00

Total weight (mg) 108.00 108.00 108.00 108.00 108.00 108.00

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Table-4: Formulation of Salbutamon Sulphate Mouth Dissolving Tablets
Prepared by Direct Compression Method (50-tablets)

Sl.
Ingredients DC1 DC2 DC3 DC4 DC5 DC6
No.

1. Salbutamol 100 100 100 100 100 100


sulphate (mg)

2. Lactose (mg) (DC) 3950 3900 3825 3725 3925 3825

3. Croscarmillose 75 125 -- -- -- --
sodium (AC-di-
Sol) (%)

4. Sodium strach -- -- 200 300 -- --


glycolate
(Explotab) (%)

5. Crospovidone -- -- -- -- 100 200


(polyplasdone)
(%)

6. Microcrystalline 1000 1000 1000 1000 1000 1000


cellulose (mg)

7. Magnesium 25 25 25 25 25 25
stearate (mg)

8. Talc (mg) 250 250 250 250 250 250

Total weight 5400.00 5400.00 5400.00 5400.00 5400.00 5400.00

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Table-5: Formulation of Salbutamol Sulphate Mouth Tablet Prepared by
Sublimation Method (1-tablet)

Sl.
Ingredients S1 S2 S3 S4 S5 S6
No.

1. Salbutamol 2.00 2.00 2.00 2.00 2.00 2.00


sulphate (mg)

2. Mannitol 78.50 77.50 76.00 74.00 78.00 76.00

3. Camphor 20.00 20.00 20.00 20.00 20.00 20.00

4. Croscarmellose 1.50 2.50 -- -- -- --


sodium (Ac-di-sol)
(%)

5. Sodium strach -- -- 4.00 6.00 -- --


glycolate
(Explotab) (%)

6. Crospovidone -- -- -- -- 2.00 4.00


(polyplasdone)
(%)

7. Magnesium 1.00 1.00 1.00 1.00 1.00 1.00


stearate (mg)

8. Talc (mg) 5.00 5.00 5.00 5.00 5.00 5.00

Total weight(mg) 108.00 108.00 108.00 108.00 108.00 108.00

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Table-6: Formulation of Salbutamol Sulphate Mouth Tablet Prepared by
Sublimation Method (50-tablets)

Sl.
Ingredients S1 S2 S3 S4 S5 S6
No.

1. Salbutamol 100 100 100 100 100 100


sulphate (mg)

2. Mannitol 3925 3875 3800 3700 3900 3800

3. Camphor 1000 1000 1000 1000 1000 1000

4. Croscarmellose 75 125 -- -- -- --
sodium (Ac-di-sol)
(%)

5. Sodium strach -- -- 200 300 -- --


glycolate
(Explotab) (%)

6. Crospovidone -- -- -- -- 100 200


(polyplasdone)
(%)

7. Magnesium 50 50 50 50 50 50
stearate (mg)

8. Talc (mg) 250 250 250 250 250 250

Total weight(mg) 5400 5400 5400 5400 5400 5400

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4.5 EVALUATION OF TABLETS:

a) Weight Variation Test3:

From each batch twenty tablets were selected at a random and average

weight was determined. Then individual tablets were weighed and the individual

weight was compared with an average weight, the variation in the weight was

expressed in terms of % deviation and the results are shown in table-7a, 7b, 8a,

8b.

b) Hardness and Friability Test3:

For each formulation the hardness was determined by using monsanto

hardness tester and Friability of the tablets was checked by using Roche

Friabilator. This device subjects a tablets to the combined effect of abrasion and

shock by utilizing plastic chamber which revolves at 25 rpm dropping the tablets

at a distance of 6 inches with an each revolution. Preweighed sample of tablets

was placed in the friabilator, which was then operated for 100 revolutions.

Tablets were dusted and reweighed and then % Friability was calculated and

shown in table-9, 10, 11, 12.

c) In Vitro Dispersion Time3:

Tablet was added to 10 ml of phosphate buffer solution pH 6.8 which

correlates pH of saliva at 37±0.5ºC and time required for complete dispersion was

noted and is shown in table-13, 14 with graphical representation in figure-5 & 6.

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d) Drug-Excipient Interaction Study:
There is always a possibility of drug-excipient interaction in any

formulation due to their intimate contact. The technique employed in this study is

IR spectroscopy. IR spectroscopy is one of the most powerful analytical

technique which offers the possibility of chemical identification. The I.R.

spectroscopy of salbutamol sulphate was obtained by KBr pellet method and

shown in figure-7 to 13.

e) Drug Content Uniformity Study4:

Five tablets were weighed individually and powdered. The powder

equivalent to 2 mg of salbutamol sulphate was weighed and extracted in

phosphate buffer pH 6.8 (100 ml) and the concentration of drug was determind by

measuring absorbance at 277nm by spectrophotometer. The results are shown in

table-15 & 16.

f) Water Absorption Ratio and Wetting Time4:

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

containing 6 ml of water. A tablet of known weight was put on the paper and the

time required for complete wetting of tablet was measured. The wetted tablet was

then weighed, water absorption ratio R was determined using the following

equation and the result is shown in table-17 & 18.

Wb – Wa
R = 100 x
Wa

Where Wb is weight of tablet before water absorption and

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Wa is weight of tablet after water absorption.

Figure-4: Schematic representation of wetting time/ water absorption ratio


determination

g) In Vitro Drug Release Study4:


Dissolution rate was studied by using USP type-II apparatus at 50 rpm

(USP XXIII Dissolution Test Apparatus) using 500 ml of phosphate buffer PH 6.8

as dissolution medium. Temperature of the dissolution medium was maintained

at 37±0.5ºC, aliquot of dissolution medium was withdrawn at every 1 minute

interval and filtered. The absorbance of filtered solution was checked by UV

spectrophotometric method at 277 nm and concentration of the drug was

determined from standard calibration curve. Dissolution rate was studied for all

designed formulations and the results are shown in table-19 & 20 with graphical

representation in figure-13 & 14.

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In vitro drug release studies details:
Apparatus used : USP XXIII dissolution test apparatus

Dissolution medium : 6.8 pH phosphate buffer solution

Dissolution medium volume : 500 ml

Temperature : 37±0.5ºC

Speed of basket paddle : 50 rpm

Sampling intervals : 1 min

Sample withdrawn : 5 ml

Absorbance measured : 277 nm

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CHAPTER–5

RESULTS

RESULTS OF WEIGHT VARIATION TEST FOR TABLETS PREPARED BY DIRECT COMPRESSION AND SUBLIMATION
METHODS
Table-7(a): Weight Variation for Direct Compression Method

DC1 DC2 DC3


Sl.
No. Weight in Difference Percent Weight in Difference Percent Weight in Difference Percent
mgs in weight Deviation mgs in weight Deviation mgs in weight Deviation
1. 107 0 0.00 108 0.8 0.74 105 -2.9 -2.68
2. 108 1 0.93 110 2.8 2.61 106 -1.9 -1.76
3. 105 -2 -1.86 105 -2.2 -2.05 107 -0.9 -0.83
4. 107 0 0.00 105 -2.2 -2.05 108 0.1 0.09
5. 107 0 0.00 106 -1.2 -1.11 108 0.1 0.09
6. 110 3 2.80 107 -0.2 -0.18 109 1.1 1.01
7. 105 -2 -1.86 106 -1.2 -1.11 108 0.1 0.09
8. 106 -1 -0.93 107 -0.2 -0.18 107 -0.9 -0.83
9. 107 0 0.00 108 0.8 0.74 107 -0.9 -0.83
10. 108 1 0.93 110 2.8 2.61 105 -2.9 -2.68
Average of 10 Tablets 107 mg Average of 10 Tablets 107.20 mg Average of 10 Tablets 107.90 mg

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Table-7(b): Weight Variation for Direct Compression Method

DC4 DC5 DC6


Sl.
No. Weight in Difference Percent Weight in Difference Percent Weight in Difference Percent
mgs in weight Deviation mgs in weight Deviation mgs in weight Deviation

1. 105 -1.7 -1.59 108 -0.2 -0.18 108 0.2 0.18

2. 106 -0.7 -0.65 107 -1.2 -1.10 109 1.2 1.11

3. 107 0.3 0.28 106 -2.2 -2.03 108 0.2 0.18

4. 108 1.3 1.21 110 1.8 1.66 107 -0.8 -0.74

5. 108 1.3 1.21 109 0.8 0.73 106 -1.8 -1.66

6. 109 2.3 2.15 108 0.2 -0.18 106 -1.8 -1.66

7. 107 0.3 0.28 109 -0.8 0.73 110 2.2 2.04

8. 106 -0.7 -0.65 108 -0.8 -0.18 108 0.2 0.18

9. 106 -0.7 -0.65 110 1.8 1.66 109 1.2 1.11

10. 105 -1.7 -1.59 107 -1.2 -1.10 107 -0.8 -0.74

Average of 10 Tablets 106.70 mg Average of 10 Tablets 108.20 mg Average of 10 Tablets 107.80 mg

50

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