Nir

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
i
Create PDF files without this message by purchasing novaPDF printer (http://www.novapdf.com)
APRIL 2006
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation/ thesis entitled MOUTH FORMULATION DISSOLVE AND EVALUATION OF OF
TABLETS
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
ii
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
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
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
v
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
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 cooperation. 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
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
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/cm, 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/cm, 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
TABLE OF CONTENTS
CHAPTER-1
INTRODUCTION ............................................................ 01-11 1.1 1.2 1.3 1.4 Desired Criteria for Mouth Dissolving Drug Delivery System........................................................... 03 Salient Features of Mouth Dissolving Tablets .............. 03 Techniques for Preparing Mouth Dissolving Tablets .... 04 Patented Technologies for Mouth Dissolving Tablets ......................................................................... 07
CHAPTER-2
OBJECTIVES .................................................................. 12-13 2.1 2.2 Need for the Study ....................................................... 12 Objectives of the Study ................................................ 13
CHAPTER-3
REVIEW OF LITERATURE .......................................... 14-34 3.1 3.2 3.3 Past work on Mouth Dissolving Tablets ....................... 14 Drug Profile ................................................................. 21 Polymer Profile............................................................ 27
CHAPTER-4
METHODOLOGY ........................................................... 35-48 4.1 4.2 4.3 4.4 4.5 Materials Used with their Source ................................. 35 Equipments .................................................................. 36 Standard Calibration Curve of Salbutamol Sulphate ..... 37 Method of Preparation of Mouth Dissolving Tablets .... 39 Evaluation of Tablets ................................................... 45
CHAPTER-5 CHAPTER-6 CHAPTER-7 CHAPTER-8 CHAPTER-9
RESULTS ......................................................................... 49-67 DISCUSSION ................................................................... 68-72 CONCLUSIONS............................................................... 73-74 SUMMARY ...................................................................... 75-76 BIBLIOGRAPHY............................................................. 77-82
x
LIST OF TABLES
Sl. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Title List of Commercially Available Orodispersible Tablets Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at max 277nm Formulation of Salbutamon Sulphate Mouth Dissolving Tablets Prepared by Direct Compression Method (1-tablet) Formulation of Salbutamon Sulphate Mouth Dissolving Tablets Prepared by Direct Compression Method (50-tablets) Formulation of Salbutamol Sulphate Mouth Tablet Prepared by Sublimation Method (1-tablet) Formulation of Salbutamol Sulphate Mouth Tablet Prepared by Sublimation Method (50-tablets) Weight Variation for Direct Compression Method Weight Variation for Sublimation Method Tablet Hardness for Direct Compression Method Tablet Hardness for Sublimation Method Percentage Friability for Direct Compression Method Percentage Friability for Sublimation Method In Vitro Dispersion Time for Direct Compression Method In Vitro Dispersion Time for Sublimation Method Drug Content for Direct Compression Method Drug Content for Sublimation Method Water Absorption Ratio and Wetting Time of Tablets Prepared by Direct Compression Method Water Absorption Ratio and Wetting Time of Tablets Prepared by Sublimation Method In vitro drug release of salbutamol sulphate by direct compression method In vitro drug release of salbutamol sulphate by Sublimation Method Page No. 11 37 41 42 43 44 49 51 53 53 54 54 55 55 64 64 65 65 66 67
xi
LIST OF FIGURES
Sl. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Title Steps involved in the development of mouth dissolving tablets by sublimation technique Standard graph of Salbutamol Sulphate in 6.8 Buffer Solution at max 277 nm Development of pores in tablet after sublimation Schematic representation of wetting time/ water absorption ratio determination Graphical representation of In Vitro Dispersion Time for Direct Compression Method Graphical representation of In Vitro Dispersion Time for Sublimation Method IR Spectra of Salbutamol Sulphate IR Spectra of Formulation DC2 IR Spectra of Formulation DC4 IR Spectra of Formulation DC6 IR Spectra of Formulation S2 IR Spectra of Formulation S4 IR Spectra of Formulation S6 Graphical representation of drug released prepared by direct compression method Graphical representation of drug released prepared by sublimation method Page No. 6 38 40 47 56 56 57 58 59 60 61 62 63 66 67
xii
CHAPTER1
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. 1
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 tablets4, 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.
2
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) iii) iv) v) vi) Be compatible with taste masking. Be portable with taste masking. Have a pleasing mouth feel. Leave minimal or no residue in the mouth after oral administration. 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. 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.
1.2
3
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
4
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 The tablets dissolve
camphor have been prepared by sublimation technique.
within 10-20 seconds and exhibit sufficient mechanical strength for practical use.
5
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. 6
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 tablets 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
7
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
8
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.
9
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 extrusionspheronization. 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
Table-1: List of Commercially Available Orodispersible Tablets11 Trade Name Feldene Fast Melt Calritin Redi Tab Maxalt MLT Zyprexia Pepcid RPD Zofran ODT Zoming-ZMT Zelpar TM Tempra Quiclets Febrectol Nimulid MDT Torrox MT Olanex Instab Romilast Benadryl Fastmelt Active Drug Piroxicam Loratidine Rizatriptan Olanzapine Famotidine Ondansetron Zolmitriptan Selegilline Acetaminophen Paracetamol Nimesulide Rofecoxib Olanzapine Montelukast Diphenhydramine and pseudoephedrine Manufacturer Pfizer Inc., USA Schering Plugh Corp, USA Merck & Co. USA Eli Lilly, Indianapolis, USA Merck & Co., NJ, USA Glaxo Wellcome, Middlesex, UK AstraZeneca, Wilmington, USA Amarin Corp., London, UK Bristol Myers Squibb, NY, USA Prographarm, Chateauneuf, France Panacea Biotech, New Delhi, India Torrent Pharmaceuticals, Ahmedabad, India Ranbaxy Labs Ltd., New Delhi, India Ranbaxy Labs Ltd., New Delhi, India Warner Lambert, USA
11
CHAPTER2
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
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.
13
CHAPTER3
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 superdisintegrants 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.
14
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.
15
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).
16
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 1005% 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.
17
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).
18
Kaushik D et al36 have prepared melt-in-mouth tablets by sublimation technique. Tablets were prepared by direct compression using directly The
compressible mannitol and ammonium bicarbonate as volatile salt.
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.
19
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.
20
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 HOH2C CH CH2NHC(CH3)3, H2SO4
Molecular weight: 288.35 Molecular formula: C13H21NO3, H2SO4 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, H2SO4 calculated with reference to the dried substance. Solubility: Soluble one in four parts of water. Slightly soluble in ethanol 96%, chloroform and ether.
21
Storage: It should be protected from light. Melting point: 150C. 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.
22
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 4-0sulphate 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.
23
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.
24
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,
25
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.
26
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.
27
Crospovidone Synonyms: Cross-linked povidone, Polyplasdone XL, PVPP, polyvinylpolypyrrolidone. 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.
28
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.
29
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.
30
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 browncolored 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 (1090% 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. 31
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 179C D , + 41 to +43 (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.
32
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 %). 33
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.
34
CHAPTER4
METHODOLOGY
4.1
Sl. No. 1. 2.
MATERIALS USED WITH THEIR SOURCE:

Material Salbutamol sulphate Croscarmellose sodium Crospovidone Sodium starch glycolate Lactose (DC) Microcrystalline cellulose Mannitol Batch No. SSI0704023 T506C Property Pure Drug Disintegrant Source Micro Labs, Bangalore Signet, Mumbai
3. 4.
94632736WO E0630
Disintegrant Disintegrant
Signet, Mumbai Signet, Mumbai
5. 6.
ES 5R 7226 --
Diluent Diluent
Eros Pharma, Bangalore Sd Fine Chemi Ltd.
7.
G04Y/0404/ 220/13 V1804041
Diluent
Loba Chemie
8.
Camphor
Sublimating agent Glidant
Sd Fine Chem Ltd.,
9.
Talc
J032/1003/ 1810/02 M-5632
Loba Chemie
10.
Magnesium stearate
Lubricant
Sd Fine Chem Ltd.,
35
4.2 Sl. No. 1. 2. 3. 4. 5. 6. 7. 8.
EQUIPMENT:
Equipment Tablet compression machine Hardness Tester Friability Test Apparatus Tablet Dissolution Test Apparatus UV Visible Spectrophotometer Oven Rotek Balance pH meter
Model CMSH/ 400/ 92 OSSCO 020334 220307 1700 97070 BT 220H 5291679
Make/Model Cadmach Single Punch compression machine Monsanto Hardness Tester Veego Digital Electrolab USP (XXIII), Bangalore Shimadzu 1700, Japan Tempo Instruments & Equipment Shimadzu Digital Balance Hanna Instruments, Italy
36
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 (mcg/ml) 00 05 10 15 20 25
Sl. No. 1. 2. 3. 4. 5. 6.
Absorbance 0.00 0.041 0.070 0.105 0.138 0.170
37
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 Concentration (mcg/ ml) 20 25 30
38
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 60C for 6 hours.
39
(a) Before Sublimation
(b) After Sublimation Figure-3: Development of pores in tablet after sublimation
40
Table-3: Formulation of Salbutamon Sulphate Mouth Dissolving Tablets Prepared by Direct Compression Method (1-tablet)
Sl. No. 1. Ingredients Salbutamol sulphate (mg) Lactose (mg) (DC) Croscarmillose sodium (AC-diSol) (%) Sodium strach glycolate (Explotab) (%) Crospovidone (polyplasdone) (%) Microcrystalline cellulose (mg) Magnesium stearate (mg) Talc (mg) Total weight (mg) DC1 2.00 DC2 2.00 DC3 2.00 DC4 2.00 DC5 2.00 DC6 2.00
2. 3.
79.00 1.50
78.00 2.50
76.50 --
74.50 --
78.50 --
76.50 --
4.
--
--
4.00
6.00
--
--
5.
--
--
--
--
2.00
4.00
6.
20.00
20.00
20.00
20.00
20.00
20.00
7.
0.50
0.50
0.50
0.50
0.50
0.50
8.
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
41
Table-4: Formulation of Salbutamon Sulphate Mouth Dissolving Tablets Prepared by Direct Compression Method (50-tablets)
Sl. No. 1. Ingredients Salbutamol sulphate (mg) Lactose (mg) (DC) Croscarmillose sodium (AC-diSol) (%) Sodium strach glycolate (Explotab) (%) Crospovidone (polyplasdone) (%) Microcrystalline cellulose (mg) Magnesium stearate (mg) Talc (mg) Total weight DC1 100 DC2 100 DC3 100 DC4 100 DC5 100 DC6 100
2. 3.
3950 75
3900 125
3825 --
3725 --
3925 --
3825 --
4.
--
--
200
300
--
--
5.
--
--
--
--
100
200
6.
1000
1000
1000
1000
1000
1000
7.
25
25
25
25
25
25
8.
250 5400.00
250 5400.00
250 5400.00
250 5400.00
250 5400.00
250 5400.00
42
Table-5: Formulation of Salbutamol Sulphate Mouth Tablet Prepared by Sublimation Method (1-tablet)
Sl. No. 1. Ingredients Salbutamol sulphate (mg) Mannitol Camphor Croscarmellose sodium (Ac-di-sol) (%) Sodium strach glycolate (Explotab) (%) Crospovidone (polyplasdone) (%) Magnesium stearate (mg) Talc (mg) Total weight(mg) S1 2.00 S2 2.00 S3 2.00 S4 2.00 S5 2.00 S6 2.00
2. 3. 4.
78.50 20.00 1.50
77.50 20.00 2.50
76.00 20.00 --
74.00 20.00 --
78.00 20.00 --
76.00 20.00 --
5.
--
--
4.00
6.00
--
--
6.
--
--
--
--
2.00
4.00
7.
1.00
1.00
1.00
1.00
1.00
1.00
8.
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
5.00 108.00
43
Table-6: Formulation of Salbutamol Sulphate Mouth Tablet Prepared by Sublimation Method (50-tablets)
Sl. No. 1. Ingredients Salbutamol sulphate (mg) Mannitol Camphor Croscarmellose sodium (Ac-di-sol) (%) Sodium strach glycolate (Explotab) (%) Crospovidone (polyplasdone) (%) Magnesium stearate (mg) Talc (mg) Total weight(mg) S1 100 S2 100 S3 100 S4 100 S5 100 S6 100
2. 3. 4.
3925 1000 75
3875 1000 125
3800 1000 --
3700 1000 --
3900 1000 --
3800 1000 --
5.
--
--
200
300
--
--
6.
--
--
--
--
100
200
7.
50
50
50
50
50
50
8.
250 5400
250 5400
250 5400
250 5400
250 5400
250 5400
44
4.5 a)
EVALUATION OF TABLETS: 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. 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. In Vitro Dispersion Time3: Tablet was added to 10 ml of phosphate buffer solution pH 6.8 which correlates pH of saliva at 370.5C and time required for complete dispersion was noted and is shown in table-13, 14 with graphical representation in figure-5 & 6.
b)
c)
45
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 The I.R.
technique which offers the possibility of chemical identification.
spectroscopy of salbutamol sulphate was obtained by KBr pellet method and shown in figure-7 to 13. Drug Content Uniformity Study4: Five tablets were weighed individually and powdered. The powder
e)
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. 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 46
f)
Wa is weight of tablet after water absorption.
Figure-4: Schematic representation of wetting time/ water absorption ratio determination 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 370.5C, 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.
g)
47
In vitro drug release studies details: Apparatus used Dissolution medium Dissolution medium volume Temperature Speed of basket paddle Sampling intervals Sample withdrawn Absorbance measured : : : : : : : : USP XXIII dissolution test apparatus 6.8 pH phosphate buffer solution 500 ml 370.5C 50 rpm 1 min 5 ml 277 nm
48
CHAPTER5
RESULTS
RESULTS OF WEIGHT VARIATION TEST FOR TABLETS PREPARED BY DIRECT COMPRESSION AND SUBLIMATION METHODS Table-7(a): Weight Variation for Direct Compression Method Sl. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. DC1 Weight in mgs 107 108 105 107 107 110 105 106 107 108 Difference in weight 0 1 -2 0 0 3 -2 -1 0 1 Percent Deviation 0.00 0.93 -1.86 0.00 0.00 2.80 -1.86 -0.93 0.00 0.93 Weight in mgs 108 110 105 105 106 107 106 107 108 110 DC2 Difference in weight 0.8 2.8 -2.2 -2.2 -1.2 -0.2 -1.2 -0.2 0.8 2.8 Percent Deviation 0.74 2.61 -2.05 -2.05 -1.11 -0.18 -1.11 -0.18 0.74 2.61 Weight in mgs 105 106 107 108 108 109 108 107 107 105 DC3 Difference in weight -2.9 -1.9 -0.9 0.1 0.1 1.1 0.1 -0.9 -0.9 -2.9 Percent Deviation -2.68 -1.76 -0.83 0.09 0.09 1.01 0.09 -0.83 -0.83 -2.68
Average of 10 Tablets 107 mg
Average of 10 Tablets 107.20 mg
49
Table-7(b): Weight Variation for Direct Compression Method DC4 Sl. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Weight in mgs 105 106 107 108 108 109 107 106 106 105 Difference in weight -1.7 -0.7 0.3 1.3 1.3 2.3 0.3 -0.7 -0.7 -1.7 Percent Deviation -1.59 -0.65 0.28 1.21 1.21 2.15 0.28 -0.65 -0.65 -1.59 Weight in mgs 108 107 106 110 109 108 109 108 110 107 DC5 Difference in weight -0.2 -1.2 -2.2 1.8 0.8 0.2 -0.8 -0.8 1.8 -1.2 Percent Deviation -0.18 -1.10 -2.03 1.66 0.73 -0.18 0.73 -0.18 1.66 -1.10 Weight in mgs 108 109 108 107 106 106 110 108 109 107 DC6 Difference in weight 0.2 1.2 0.2 -0.8 -1.8 -1.8 2.2 0.2 1.2 -0.8 Percent Deviation 0.18 1.11 0.18 -0.74 -1.66 -1.66 2.04 0.18 1.11 -0.74
50

Nir

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Nir

Uploaded by

Copyright:

Available Formats

FORMULATION AND EVALUATION OF MOUTH DISSOLVE TABLETS OF SALBUTAMOL SULPHATE

MASTER OF PHARMACY in PHARMACEUTICS

Under the Guidance of

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

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

DECLARATION BY THE CANDIDATE

Date: Place: GULBARGA

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

CERTIFICATE BY THE GUIDE

Date: Place: GULBARGA S.S.BUSHETTI

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ENDORSEMENT BY THE HOD, PRINCIPAL/ HEAD OF THE INSTITUTION

Date: Place: GULBARGA Prof.Syed Sanaullah

COPYRIGHT DECLARATION BY THE CANDIDATE

Date: Place: GULBARGA

Rajiv Gandhi University of Health Sciences, Karnataka

Date: Place: Gulbarga

LIST OF ABBREVIATIONS USED

CHAPTER-5 CHAPTER-6 CHAPTER-7 CHAPTER-8 CHAPTER-9

bioavailability by avoiding first pass liver metabolism3.

camphor have been prepared by sublimation technique.

PATENTED TECHNOLOGIES FOR MOUTH DISSOLVING TABLETS:

oxyphenbutazone were formulated using potato starch or microcrystalline cellulose as disintegrants.

compressible mannitol and ammonium bicarbonate as volatile salt.

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

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

Stability: Mannitol is stable in the dry state.

Incompatibilities: None reported in the dry state.

ethanol, synthetic, optically inactive).

MATERIALS USED WITH THEIR SOURCE:

Signet, Mumbai Signet, Mumbai

Eros Pharma, Bangalore Sd Fine Chemi Ltd.

G04Y/0404/ 220/13 V1804041

Sublimating agent Glidant

Sd Fine Chem Ltd.,

J032/1003/ 1810/02 M-5632

Sd Fine Chem Ltd.,

4.2 Sl. No. 1. 2. 3. 4. 5. 6. 7. 8.

Absorbance 0.00 0.041 0.070 0.105 0.138 0.170

0.1 0.08 0.06 0.04 0.02 0 0 5 10 15 Concentration (mcg/ ml) 20 25 30

The ingredients after sifting thoroughly mixed for 10 minutes.

subjected to sublimation at 60C for 6 hours.

(a) Before Sublimation

(b) After Sublimation Figure-3: Development of pores in tablet after sublimation

78.50 20.00 1.50

77.50 20.00 2.50

3875 1000 125

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

technique which offers the possibility of chemical identification.

Wa is weight of tablet after water absorption.

Average of 10 Tablets 107 mg

Average of 10 Tablets 107.20 mg

Average of 10 Tablets 107.90 mg

Average of 10 Tablets 106.70 mg

Average of 10 Tablets 108.20 mg

Average of 10 Tablets 107.80 mg

You might also like