DESIGN AND EVALUATION OF TERBUTALINE SULPHATE CONVENTIONAL TABLETS BY FLUIDIZED BED GRANULATION TECHNOLOGY

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

SUBMITTED BY

Mr. BADALA MOHAN REDDY

M.PHARM Ist YEAR

DEPARTMENT OF PHARMACEUTICS

UNDER THE GUIDANCE

Mrs. SAYANI BHATTACHARYYA, M.Pharm.,

THE OXFORD COLLEGE OF PHARMACY

BANGALORE-68.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE – II

Proforma for Registration of Subject for Dissertation

1. / Name of the candidate and address / BADALA MOHAN REDDY
A.POSTAL ADDRESS
THE OXFORD COLLEGE OF PHARMACY NO.6/9,1ST CROSS,
BEGUR ROAD,HONGASANDRA,
BENGALURU-560 068,KARNATAKA.
B.PERMANENT ADDRESS
S/O BADALA BOJANNA, H.NO 2-66,
MENDORA(VIL), BALKONDA(MDL)
NIZAMABAD(DIST), ANDHRAPRADESH
PIN:503219
2. / Name of the institution / THE OXFORD COLLEG OF PHARMACY,NO.6/9,1ST CROSS,
BEGUR ROAD,HONGASANDRA,
BENGALURU-560 068,
KARNATAKA.
3. / Course of study and subject / Master of Pharmacy in Pharmaceutics
4. / Date of admission to course / 18/10/ 2010
5. / Title of the topic:
DESIGN AND EVALUATION OF TERBUTALINE SULPHATE CONVENTIONAL TABLETS BY FLUIDIZED BED GRANULATION TECHNOLOGY

6.0 BRIEF RESUME OF THE INTENDE WORK:

6.1 Need for the study

Asthma is an inflammatory disorder of the airways, which causes attacks of wheezing, shortness of breath, chest tightness, and coughing.

Most solid products in the pharmaceutical industry are manufactured using the fluidized bed granulation, and it is a complex multi-factorial system.

The anti-asthmatic drug shows short biological half life, short duration of action and poor bio-availability when prepared by conventional process, so we can prepare tablets by fluidized bed granulation to overcome such problems1.

The oral drug delivery system prepared by using fluidized bed drying method, produces a possibility of achieving long lasting effect and reliable release of drug at a desired rate.

The oral anti asthmatic tablets prepared by fluidized bed process technology administered principally in patients who are unable to use inhaled bronchodilator because the inhalers that contain drugs, which provide a short-term effect.

The oral Bronchodilating agents are administered in children to relieve acute bronchospasm ,who are unable to use inhalers.

The fluidized bed can be used to dry the wet product, granulation, agglomerate particles, improve flow properties, instantize the product, or produce coated particles for controlled release or taste masking, rotary pelletization, and powder and solution layering 2.

Fluidized bed granulation is an established choice for improving the processing properties of pharmaceutical powders, such as

  • Render material free-flowing
  • Densify materials
  • Prepare uniform mixes which do not seggregate
  • Improve the compression characteristics of the drug
  • Control the rate of drug release
  • Facilitate volume dispensing
  • Reduce dust
  • Improve the appearance of a product
  • Reduce variations in different batches of raw materials3.

The production of tablets of high quality in large scale production requires a tablet mass with excellent properties regarding mixing homogeneity and flowability, both of which are improved by fluidized process technology.

Improves homogeneity in the subsequent mixing processes and ultimately prevents segregation in the hopper, facilitating tablet weight and dose uniformity during tablet preparation.

The Fluidized bed granulation process has many advantages over conventional wet massing. They are

  • Simplification of tablet manufacturing procedures by possible elimination of grinding steps.
  • All the granulation processes, which require separate equipment in the conventional method, are performed in one unit, saving labour costs, transfer losses and time.
  • Another advantage is that the process can be automated once the conditions affecting the granulation have been optimized4.
  • Review of literature
  1. TheConventional Terbutaline sulphate (TS) tablets not only produce rapid and relatively high peak blood levels resulting in adverseeffects but also should be administered 3 to 4 times daily. These drawbacks can be overcome by designing a suitable mucoadhesivesustained-release TS preparation. Several synthetic polymers are in use for this purpose. Since the biodegradability of the syntheticpolymers are questionable, in this investigation an oral mucoadhesive controlled delivery system has been developed for TS usingnatural mucoadhesive materials extracted from the edible fruits like Zizyphus mauritiana (ZM), Tamarindus indica (TI) and Aeglemarmelos (Linn.) Cor (AM).The matrix tablets containing75% mucoadhesive materials extracted from AM exhibited suitable release kinetics and uniform absorption characteristics comparable tothat of Theobric SR®. This formulation produced a smooth and extended absorption phase very much similar to that of Theobric SR1.
  2. Formulation of low dose content drug of Diclofenac sodium in fluidized bed granulator by using Corbopol 934P solution(1%w/v) as a granulating solution in the fluidized bed granulator to achieve acceptable content uniformity. They also compared dissolution study of tablets prepared by direct compression and wet granulation.Tablets prepared by fluid bed granulation technique prolonged the release of Diclofenac Sodium better than tablets obtained by direct compression and wet granulation5.
  3. Development of once-daily extended release tablet of Lamotrigine, by rapid mixer granulator and fluidized bed granulator using hydrophilic matrix material (Methocel K4M & Methocel K100LV) in combination with hydrophobic material (Eudragit L-30D- 55) were used, which can release the drug upto 24hrs in predetermined rate. Prepared tablets were evaluated for certain physical properties like Tablet wt. variation, hardness, thickness, friability, dissolution study, Assay, etc.The granules showed satisfactory flow properties, compressibility, and drug content6.
  4. Preparation of mini-tablets with 3 mm diameter containing metoprolol tartrate as active ingredient by fluidized bed granulation of components with the formulation of 20% of the active drug, lactose as filler for fluid bed granulation, Cellactose 80 as extra granular diluent, as well as magnesium stearate and Compritol as lubricants. They can be used either as pediatric medication or adult medication after further coatings, in order to obtain modified release mini-tablets. They were evaluated and the results were no sticking, uniformity of weight and content uniformity in required limits, as well as desired immediate release of the drug was obtained7.
  5. Establishment of the combined release behaviour from a novel Propranolol HCl Sustained-release pellets (SRPs) and Flunarizine dihydrochloride immediate release mini tablet (IRMT) by fluidized bed processing in the form of capsule. The hydrophobic & hydrophilic polymer like EC 50 cps and HPMC E-15 in ratio 85:15/80:20 was found to play a great role in rate controlling of Propranolol HCl 40mg SRPs formulation were developed using fluid bed layering and coating techniques (FBP), IRMT formulation were developed by wet granulation. The dissolution data of SR Pellets formulation showed good fit in Higuchi’s equation which indicated the best linearity and also showed a tendency to follow near zero order kinetic andIR mini tablet showed good fit in Korsmeyer-Peppas model kinetic and followed by first order kinetic drugrelease which indicated the effect of Super case-II transportdiffusion mechanism, DSC study revealed that there was no chemical interaction between drug & excipients8.
  6. Development of immediate release solid oral formulations of Telmisartan which can be prepared using Fluidized bed granulation. And the formulation showed long-lasting stability under different climatic conditions and sufficient solubility of the active substance for sufficient gastrointestinal absorption in the slightly acidic and neutral pH region, and dissolution showing no essential pH dependency Tablets were evaluated for various parameters like, weight variation, content uniformity, in-vitro dissolution studies were performed using United States Pharmacopeia (USP) apparatus type II9.
  7. Successfully developed rapidly disintegrating tablets containing a large quantity of an intensely bitter drug developed with Layering a large quantity of the drug on the fine microcrystalline cellulose spheres (FMCS) (Celphere SCP-100) as seed cores, by fluidized bed processing.The layered micro granules were coated with the microcrystalline cellulose (MCC) (Ceolus KG-802), ethylcellulose aqueous dispersion (ECAD) (Celioscoat EC-30A) as taste masking film coating liquid using modified Wurster fluidized bed apparatus. The tablet evaluated for hardness, disintegration property, dissolution profile and mouth feels10.
  8. Frmulation of sublingual tablets of terbutaline for rapid action, and to improve both bioavailability and patient compliance to therapy. A wet granulation technique was adapted to prepare the granules. The results obtained showed that the quantity of microcrystalline cellulose (MCC) and crospovidone significantly affect response variables. The results indicate that the inclusion of crospovidone, a bioadhesive component, in sublingual tablet formulations, makes the swallowing of tablets unnecessary, because the release and absorption of the terbutaline in such formulations is acceptably effective11.
  9. Fluid-bed granulation recently emerging innovative technologies are being developed to improve the fluid-bed granulation process, process control and process robustness. Granulation process are applied to improve flowability, improve compressibility, improve uniformity, improve wettability, densification and easier to disperse or transfer12.
  10. The manufacturing method of the tablets involved in the crystalline transition of amorphous sucrose that was produced in the process of fluidized bed granulation of mannitol using sucrose solution as a binder. This is used to clarify the usefulness of amorphous sucrose formed during the granulation for the rapidly disintegrating oral tablets manufacturing, and to investigate the effects of crystalline transition of the amorphous sucrose in granules on the characteristics of the resultant tablets prepared by this crystalline transition (CT) method. We conclude that rapidly disintegrating oral tablets can effectively be manufactured by the CT method using the granules obtained by the fluidized bed granulation method13.
  11. Designingof a new orally disintegrating tablet (ODT) that has high tablet hardness and a fast oral disintegration rate using fluidized-bed granulator . To obtain rapid disintegration granules (RDGs), a saccharide, such as trehalose, mannitol, or lactose, was spray-coated with a suspension of corn starch using a fluidized-bed granulator . As an additional disintegrant, crospovidone, light anhydrous silicic acid, or hydroxypropyl starch was also included in the suspension. The RDGs obtained possessed extremely large surface areas, narrow particle size distribution, and numerous micro-pores. When tabletting these RDGs, it was found that the RDGs increased tablet hardness by decreasing plastic deformation and increasing the contact frequency between granules. Mannitol spray-coated with a suspension of corn starch and crospovidone (2.5:1 w/w ratio) showed most appropriate properties for ODTs. In conclusion, this simple method to prepare superior formulations for new ODTs was established by fluidized bed granulation of spray-coating mannitol with a suspension of appropriate disintegrate14.
  12. Evaluation and comparison of the functionality of bovine fatty acids derived (MgSt-B) and vegetable fatty acids-derived (MgSt-V) magnesium stearate powders when used for the lubrication of granules prepared by high-shear (HSG) and fluid bed (FBG) wet granulation methods. The work included evaluation of tablet compression and ejection forces during tabletting and dissolution testing of the compressed tablets15.
  13. Investigation of the possibility of using a Carbopol polymeric solution as granulating agent by the fluid bed granulating process; select a suitable method of tabletting for sustaining the release of ketoprofen for 12hr; they performed stability studies according to International Committee on Harmonization (ICH) guidelines and photo stability on ketoprofen SR tablets; to studied the influence of the storage conditions on release kinetics and melting endotherm of ketoprofen; and predicted the shelf-life of the ketoprofen SR tablets. Tablets prepared by fluid bed granulation technique prolonged the release of ketoprofen better than tablets obtained by direct compression and wet granulation16 .

6.3 Objectives of the study

In the present work attempt will be made to

  1. To Carry out pre-formulation studies, it include

1)Compatibility

2)Particle size analysis.

3)Flow property of the granules.

4)Compressibility and Hausner ratio.

  1. In case of tablet evaluation following studies are involved,

1)General appearance

2)Size and shape

3)Organoleptic properties

4)Hardness test

5)Friability test

6)Weight variation test

7)Content uniformity

8)Disintegration test

9)Dissolution test

10)Stability studies.

7.0 Materials and Methods

Drug : Terbutaline sulphate

Polymer : PVP, PVP K80

Method : Fluidized bed granulation, Rapid mixer granulation.

7.1 Source of data:

Data was obtained from drug invention today, Pub med, Science direct, Medline, US patent office, Helinet, World wide wedsite,Literature search and Related Articles from library of The Oxford College Of Pharmacy.

7.2Method of collection of data

  1. Compatibility study by FTIR/IR
  1. Preparation of reproducible batches of formulations
  2. Evaluation

Flow property

Size and shape

Hardness test

Friability test

Weight variation test

Content uniformity

Disintegration test

Dissolution test

Stability studies.

7.3 Does the study require any investigation or interventions to be conducted on patients or other humans or animals?

No Applicable.

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

No Applicable.

8. Reference

  1. Chandaa R, Roy A, Bahadur S, Sahab S, Das S, Choudhury A. Formulation of terbutaline sulphate mucoadhesive sustained release oral tablets from natural materials andin-vitro, in-vivoevaluation.Asian J.Pharmaceutical Sciences 2010; 5 (4): 168-174.
  2. Doelling MK, Nash RA.The Development of a Microwave Fluid Bed Processor II, Drying Performance and Physical Characteristics of Typical Pharmaceutical Granulations. Pharm. Res1992; 9 (11): 1493-1501.
  3. Lipsanen T .Process analytical technology approach on fluidized bed granulation and drying.November 8th, Helsinki 2008; 1-59.
  4. Summers M, Aulton M.Dosage form design and manufacture- Introduction to Granulation 2002:364-377.
  5. Patel T, Patel LD, Patel T, Makwana S, Patel T. Studies in Formulation Development of Low Dose Content Drug Using Fluid Bed Granulation Technique.J. Pharmaceutical sciences and research2010;2(4): 264-271.
  6. Chowdary A.Formulation and development of extended released tablets of Lamotrigine.International J. Pharma and Bio Sciences2011; 2: 198-210.
  7. Mirelabodea, Tomuta I, leucuta S.Identification of critical formulation variables for obtaining metoprolol tartarate mini tablets. Formacia 2010, 58( 6): 719-727.
  8. Patil D, Sajeeth CI, Sirwani R, Santhi K.Modulation of Combined Release Behaviours from a Novel Pellets and Mini Tablet in Capsule System. International J. Research in Pharmaceutical and Biomedical Sciences 2011; 2 (2): 649-660.
  9. Parikh BN, Patel DM, Patel CN, Dave JB, Gothi, GD Patel.Formulation optimization and evaluation of immediate release tablet of Telmisartan. J.Global Pharma Technology 2010; 2(2): 79-84.
  10. Yaginuma Y, Yoshida N. Preparing rapid disintegrating tablets containing taste-masking microgranules. Pharm. Tech 2005; 29(10): 136–150.
  11. Narengra C, Srinath MS, Rao PB.Formulation and evaluation of a sublingual tablet containing terbutaline sulphate, optimisation and in vivo studies. Ars Pharmaceutica 2005; 46(2): 139-158.
  12. Ezhilmuthu RP, Senthilkumar KL, Vasanthan A, Vimalan G, Chenchuratnam B.Process development and scale up of fluid bed granulation process. International J.pharma research and development 2011; 3: 45-49.
  13. Sugimoto M, Narisawa S, Matsubara K, Yoshino H, Nakano M, Handa T.Development of manufacturing method for rapidly disintegrating oral tablets using the crystalline transition of amorphous sucrose.International J. Pharmaceutics2006; 320:71-78.
  14. Okuda Y, Irisawa, Okimoto K, Osawa T, Yamashita S. A new formulation for orally disintegrating tablets using a suspension spray-coating method. International J. Pharmaceutics 2009; 382(2): 80-87.
  15. Gupta A, Mazen L, Hamad, Tawakkul M, Vilayat A, Sayeed, Mansoor AK. Difference in the Lubrication Efficiency of Bovine and Vegetable-Derived. AAPS Pharm SciTech 2009; 10(2): 500–504.
  16. VaithiyalingamSR,Tuliani P,WilberW,ReddyIK,KhanMA.Formulation and Stability Evaluation of Ketoprofen Sustained-Release Tablets Prepared by fluid Bed Granulation with-Carbopol 971P Solution. Industrial pharma2002; 28(10): 1231-1240.

9. / Signature of the Candidate / ( B.MOHAN REDDY)
10. / Remarks of the Guide: DESIGN AND EVALUATION OF TERBUTALINE SULPHATE CONVENTIONAL ANTIASTHMATIC TABLETS BY FLUIDIZED BED GRANULATION TECHNOLOGY, of M.Pharm has been discussed and worked under my direction and supervision as a official guide. Theprogram and research work envisaged is of great importance in the modern field of Pharmaceutical research...
11. / Name & Designation (in BLOCK LETTERS)
11.1 Guide / Mrs. SAYANI BHATTACHARYYA
11.2 Signature of Guide
11.3 Co-guide / Mr. B S HARISH PRASHAD
MANAGER-FORMULATIONS DEVELOPMENT ,
ASTRAZENECA PHARMA INDIA LTD.
11.4 Signature of co-guide
11.5 Head of the Department / Dr. KALYANI PRAKASAM
11.6 Signature of HOD:
12. / 12.1 Remarks of the Principal: The above mentioned information is correct and I recommend the same for approval.R
12.2 Principal
12.3 Signature of the Principal / Dr. PADMAA M PAARAKH

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