Design and Evaluation of Orodispersible

DESIGN AND EVALUATION OF ORODISPERSIBLE

TABLETS OF AZELASTINE HYDROCLORIDE

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BENGALURU, KARNATAKA.

By

SIDDRAMAPPA KACHERI

Under the guidance of

Mr.BASAWARAJ BENDEGUMBLE

M. Pharm., (Ph. D)

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY

H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF

PHARMACEUTICAL SCIENCES, SEDAM ROAD,

GULBARGA- 585105.

2013-2014

1

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCE, KARNATAKA

BANGALORE

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate
(In block letters) / SIDDRAMAPPA
Permanent address / S/O RAJASHEKHAR KACHERI R/O KAMALAPUR, PIN-585313, TQ-GULBARGA
DIST-GULBARGA
KARNATAKA
2. / Name of the institution / H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES, SEDAM ROAD,
GULBARGA-585105.
3. / Course of study and subjects / M.PHARM
(PHARMACEUTICAL TECHNOLOGY)
4. / Date of admission to the course / 30-07-2013
5. / Title of the topic / DESIGN AND EVALUATION OF ORODISPERSIBLE TABLTES OF AZELASTINE HYDROCHLORIDE.
6 / Brief resume of the intended work
6.1 / Need for the study:
The concept of orodispersible or mouth dissolving drug delivery system emerged from the desire to provide patient with more conventional means of taking the medication. The patients having difficulty in swallowing, these tablets disintegrates in the mouth and this could enhance the effect of drug through pre-gastric absorption from the mouth, pharynx and oesophagus, in such cases bioavailability of drug is significantly greater than those absorbed from conventional tablet dosage form1.
In some cases, such as motion sickness, sudden episodes of allergic attack and unavailability of water, swallowing conventional tablets may be difficult. Such problems can be over-come by means of fast dissolving tablets which are prepared by using natural disintegrants which easily dissolves in saliva2.
Where patients may not have ready access to water in such patients they overcome the swallowing difficulty associated with, pediatric or geriatric. Thus it provides convenience of administration. Greater patient compliance and quick onset of action. Therefore, in the present study an attempt will be made to formulate orodispersible tablets of azelastine hydrochloride. It is a anti-allergic drug with a view to provide a convenient means of administrations to those patients suffering from difficulties in swallowing such as pediatric, geriatric, unco-operative and patients3.
The aim of present work is to develop an orodispersible tablet of Azelastine hydrochloride for the effective treatment of allergic condition. Azelastine hydrochloride is a histamine antagonist drug which is mainly used to treat allergic reaction .It is well absorbed after oral administration. The bioavailability is 40% and half-life is about 25 hours increasing to 35.5 hours after multiple dose4.
6.2 / Review of Literature
Literature review shows that no published report of work on mouth dissolving tablets of anti-hypertensive drug using natural and blend of synthetic disintegrants. Some of the published articles on similar works for various medicinal agents are done.
Sudheshnababu S, Sai kishore V. Prepared amlodipine besylate fast disintegrating tablets using natural polymers like Fenugreek seed mucilage and Ocimum basilicum gum as a natural superdisintegrating agents to achieve quick onset of action, is to increase the water uptake with in shortest wetting time and there by decrease the disintegration time of the tablets by simple and cost effective direct compression technique. The hardness, friability and drug content of all the formulations were found within the limits. The Best formulations FFGK5 & FOB5 showed good disintegration time, hardness and friability. The promising formulations were also found to be stable. Optimized formulations were subjected to stability studies as per ICH guidelines5.
Sudhir B. Designed fast dissolving tablet of diclofenac sodium using sugars i.e. Sorbitol, Mannitol and polymers like HPMC, PVP by direct compression technique. The fast dissolving tablets were formulated by pure drug as well as solid dispersion of drug and beta-cyclodextrin. The tablets were evaluated for hardness, friability, weight variation, in-vitro dispersion time and in-vitro dissolution study. The stability studies showed no significant variations in all the parameters and were found to be stable. Concluded that the fast dissolving tablet of poorly soluble drug can be made by direct compression technique using selective super disintegrates and solid dispersion showed enhanced dissolution and hence better patient compliance for effective therapy6.
Biraju P, Dhaval P, Ramesh P, Chirag P, Sanja SD. Fabricated fast dissolving tablets of glipizide by direct compression method to improve patient compliance. Superdisintegrants like crospovidone and croscarmellose sodium (4%, 5%, 6%) with different binders such as PVP K30 and pregelatinized starch (3%) were used. The prepared batches of tablets were evaluated for hardness, friability, weight variation, disintegration, wetting time, drug content and in- vitro dissolution studies. Formulation prepared by using 5% croscarmellose sodium with 3% PVP K30 was selected as optimized formulation and was compared with marketed conventional formulation. Stability studies carried out at 25ºC / 60% RH and 40ºC / 75% RH for optimized formulation for 2 months7.
Ashish G, Gupta MM. Have formulated and masked the taste of Levocetrizine dihydrochloride mouth dissolving tablets using Kyron T-134 (ion exchange resin) as taste masking agent. Results show that effective taste masking is achieved for Levocetrizine dihydrocloride by preparing drug-resin complex using Kyron T-134. The tablets have evaluated for the drug content, weight variation, and water absorption ratio, wetting time, in-vitro disintegration, hardness, friability, thickness uniformity and in-vitro dissolution. The tablets disintegrated in-vitro within 29 to 59 seconds. In-vitro drug release profile of tablets is showed 99% drug release in 10 minutes. The results concluded that Levocetirizine dihydrochloride can be successfully formulated into a mouth dissolving tablet8.
Suhas MK and Ketan B, et al. Formulated the mouth dissolving tablets of losartan potassium to provide a quick onset of action. Mouth dissolving tablets prepared by direct compression and using super disintegrants like Polyplasdone XL10 Croscarmellose sodium and Explotab in different concentration and evaluated for the pre-compression parameters such as bulk density, compressibility, angle of repose etc. The prepared batches of tablets were evaluated for post compression parameters and foundsatisfactory. Amongall, theformulationF3containing5%w/wsuperdisintegrantsPolyplasdoneXL10 was considered tobebestformulation, whichreleases drug upto99.26%in12min9.
Rameshwari S, Jeya AJ. Evaluated the effect of increasing nifedipine load on the characteristics of fast-disintegrating sublingual tablets using superdistintegrants like croscarmellose sodium, sodium starch glycolate, crospovidone. Three different groups of formulations (A, R, and V) with variation in tablet excipients were prepared by direct compression method. quality control tests like weight variation, hardness, friability, drug content, disintegration time and dissolution time were evaluated for each formulation and found satisfactory. The studied sublingual tablet group V shows a lesser T50% compared to commercial oral tablet. The Group V also indicates the fast dissolution and disintegration rate of the optimized nifedipine sublingual tablet, which is must for rapid management of anginal and hypertension diseases10.
Mukesh G, Madhabai P, Avani A, Ruchi A, and Neha B. They formulated fast dissolving tablets of nimesulide, granules were formed containing nimesulide, camphor, crospovidone and lactose were prepared by wet granulationtechnique. The tablets were evaluated for friability, wetting time, and disintegration time. The tablets should be prepared using anoptimum concentration of camphor and a higher percentage of crospovidone. A checkpoint batch was also prepared to prove the validity of the evolved mathematical model. Sublimation of camphor from tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum. The systematicformulation approach helped in understanding the effect of formulation processing variables11.
Shailendra kumar S, Dina Nath M,Rishab J , Pankaj J. Have prepared fast disintegrating combination tablets of Omeprazole and Domperidone by using pertinent disintegrant. The tablets were prepared using mannitol as diluent and sodium saccharin as sweetening agent along with three different levels of disintegrant. The superdisintegrant used in this study were Kollidon CL, Ac-Di-Sol and SSG. They can be concluded that the formulation prepared with 4.76%Ac-Di-Sol (internally cross linked form of sodium carboxymethylcellulose) i.e. 10 mg showed. Disintegration time of 15 seconds in-vitro. Also the hardness, friability, dissolution rate and assay of prepared tablets were found to be acceptable according to standard limits12.
Kushal P and Ashwini R. They have formulated the preparation of telmisartan (TLM) mouth dissolving tablets were prepared using skimmed milk powder (SMP) and poloxamer-188 (PXM-188) as carriers and crosspovidone as superdisintegrant. Mouth dissolving tablets should show fast disintegration, dissolution, ease of swallowing, quick on set of action. The prepared formulations were subjected to FTIR, DSC and XRD studies. The result indicated no interaction between drug and carriers. The XRD results showed that the drug was converted into amorphous form and uniformly dispersed throughout the carriers13.
Jain CP and Naruka PS. In this investigation fast dissolving tablets of valsartan were prepared using different superdisintegrants by direct compression method. FDTs were evaluated for physicochemical properties and in-vitro dissolution. Effect of disintegrant on disintegration behavior of tablet in artificial saliva, pH 5.8 was evaluated. Wetting time of formulations containing Crospovidone was least and tablets showed fastest disintegration. The drug release from FDTs increased with increasing concentration of superdisintegrants and was found to be highest with formulations containing Crospovidone. The release of valsartan from FDTs was found to follow non-Fickian diffusion kinetics14.
Khatoon N, Ragvendra Rao GN et al. They discuss that fast dissolving oral films have several advantage over conventional dosage form. So they are of great importance during the emergency cases. Such as allergic reaction and asthmatic attack whenever immediate onset of action is desired.They offer many advantage over the other dosage form as well as easy production and evaluation technique15.
Malviya R, Pranati S, Sharma PK. Have carried out extraction and evaluation of mango peel pectin as a disintegrating agent. Tablet of mango peel pectin had comparatively lesser release of drug as compared to sodium starch glycolate for a specific period of time. Therefore mango peel pectin can’t be used as a promising disintegrant, but due to its good solubility in biological fluid and better swelling index, it can be used to prepare orodispersible tablet16.
Parashar B, Yadav V et al. fast dissolving tablets constitute an innovative dosage form, which overcome the problem of swallowing and provides quick onset of action. The paediatric and geriatric populationsare the primary, targets, as both the groups found it difficult to swallow conventional tablets. Formulation achieved rapid disintegration and instatenous dissolution of the tablet along with good taste masking properties and excellent mechanical strength17.
Nitin CM, Adhikrao VY, Vaishali KG. Fabricated orodispersible tablets of metronidazole by three different techniques of taste masking and three different disintegrating agents’ viz. sodium starch glycolate (SSG), bamboomanna (BM), chitosan (CHN) and combination thereof. All the formulations were evaluated for their pharmaceutical and clinical efficacy and among these formulations, the combination of SSG: BM and SSG: CHN in ratio 1:1 showed good results.Concluded that metronidazole is a choice of drug in most of the oro-dental problems. The Pleasantly flavored and taste masked orodispersible metronidazole in tablet form helps to overcome the drawbacks and increases patient compliance18.
Masareddy RS,Kadia RV,Manvi FV. Designed mouth dissolving tablets of clozapine, in view of enhancing bioavailability using two different methods direct compression and sublimation. All prepared formulations were evaluated for physico-chemical parameters. The formulations exhibited good disintegration properties with total disintegration time in the range of 25 to 35 s. Comparison proved direct compression method is a better alternative to sublimation method as its formulations rapidly disintegrate in oral cavity.In-vitrocumulative percentage drug release for formulations prepared by direct compression with explotab superdisintegrants shows 99.79% while sublimation method using camphor 93.58% release in 12 min19.
6.3 / Objectives of the study
In the proposed research work Orodispersible tablet will be prepared using either novel/natural disintegrants / co-processed excipients by one or more methods such as effervescent, sublimation, disintegrant addition or use of sugar based excipients etc. The orodispersible tablets will be prepared with an objective of
i)Improves bioavailability of the drug by passing first pass metabolism.
ii)It gives quick onset of action.
iii)To allow high drug loading.
iv)Requires no water intake.
v)Better patient compliance.
The prepared formulations will be evaluated for hardness, friability, weight variation, disintegration time, drug content, short-term stability, wetting ability in-vitro dissolution study and drug excipient interaction.
7. / Materials and Methods
7.1
7.2 / Source of Data:

• Internet
• National and international journals
• Gulbarga university library, Gulbarga.

Materials used:
Disintegrants like crospovidone, croscarmellose sodium, sodium starch glycolate, LHPC11 microcrystalline cellulose. Similarly, various natural disintegrants. such as moringa alifiria cucurbita maxima pulp, sophera, fenu greek linn seed natural gum, modified starch, gum karaya and cassia fistula.
7.3 / Preparation of Fast dissolving Tablets by various techniques:
By Direct compression: In this method the drug is directly compressed with the super disintegrants such as natural gums, like linn seed, modified starch, gum karaya and fenu greek etc and binders, lubricants . This usually done to the drug which is in the granule form.
Sublimation: In this method, mannitol is used as a diluent and camphor as a volatile material. After compression, the tablets will be heated in hot air oven at 500C until a constant weight is obtained ensure the complete removal of volatile component.
Mass extrusion technique:This technology involves softening the active blend using the solvent mixture of water-soluble polyethylene glycol and methanol and subsequent expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablet. The dried cylinder can also be used to coat granules for bitter drugs and thereby achieve taste masking.
Spray drying technique: In this technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a bulkingagent and sodium starch glycolate or crosscarmellose or crospovidone are used assuperdisintegrants. Tablets manufactured from the spray-dried powder have been reported todisintegrate in less than 20 seconds in aqueous medium.This spray-dried powder, which compressed into tablets showed rapiddisintegration and enhanced dissolution.
Addition of disintegrant: In this method, super disintegrants such as sodium starch glycolate, cross linked polymers, cross linked PVP, linn seed etc will be included to obtain disintegration.
Evaluation of fast dissolving: ESTIMATION OF DRUG CONTENT:
The drug content of fast dissolving will be determined spectrophotometric method.
Pre compression parameter:
Angle of repose, Bulk density, bulkiness, void volume, porosity.
Angle of repose
The angle of repose will be deterimined by the funnel method suggested by newman. Angle of repose is determined by the following formula
Tan θ = h/r
Therefore = tan -1 h/r
Where, h = height of cone
r = radius of the cone base
Angle of repose less than 300 shows the free flowing of the material.
Bulkiness
Specific bulk volume or reciprocal of bulk density is called bulkiness or bulk. Bulkiness increase with a decrease in particle size. In mixture of material of different sizes, however the smaller particle shift between larger particle and tend to reduce the bulkiness. The bulkiness can be calculated by following formula
Bulkiness = I/Pb
Where, Pb = Bulk density
Void volume
The volume of the spaces is known as the void volume “V” and is given by the formula
V = Vb – Vp
Where, Vb = Bulk volume (volume before tapping)
Vp = True volume (volume after tapping)
Porosity
The porosity (€) of powder is defined as the ratio of void volume to the bulk volume after packing.
The porosity of powder is given as
% € = (1 – VP/Vb) × 100
The porosity of powder indicates the types of packing powder undergoes when subjected to vibration, when stored or in tablet machine, when passed through hopper or feed frame.
Bulk density
Bulk density is defined as the mass of the powder divided by void volume and is expressed as gm/cm3.The bulk density of powder primarily depend upon particle size distribution, particle shape and the tendency of particle to adhere together. The particles pack in such a way so as to leave large gaps between their surfaces resulting up in light powder of low bulk density. Bulk density is very important in the size of containers needed for handling, shipping and storage of raw material and blend. It is also important in size blending equipment.
Pb = M/VP
Pb = Bulk density
M = weight of sample in gm.
V = final volume of blend in cm3
Disintegration time:
Disintegration time of fast dissolving tablets can be determined by using distilled water at 37±20C as a medium using tablet disintegration test apparatus BP.
In-vitro dissolution study:
In-vitro drug release study of prepared fast dissolving tablets will be carried out in 900 ml of pH 6.8 phosphate buffer in the USP XXII tablet dissolution tester.
8. / List of Reference

1. Ved Prakash, Saurabh M, Deepika, Shiv Kumar Y, Hemlata, and Vikas Jogpal. Fast disintegrating tablets: Opportunity in drug delivery system, J Adv pharm. Technol. 2011;2(4): 223-235.
2. Pooja A,Vandana S. Orodispersible tablets: A comprehensive review. Int.J.Res.Dev. Pharm. L, 2013;2(2): 270-284.
3. Yourong Fu, Schichung Y, Seong HJ, Susumu K, and Kinam P. Orally fast disintegrating tablets: Developments, Technologies, Taste-masking and clinical studies. 2004;21(6): 433-475.
4. Martindale: The complete drug reference, 35th edition, London: Pharmaceutical press 2007; 1: 513.
5. Sudeshnababa S, Sai Kishore V. International current pharmaceutical journal. 2012;1(9):243-249.
6. Sudhir B, International journal of bio-chemical and pharmaceutical research. 2011; 3(1): 606-616.
7. Biraju P, Dhaval P, et al. International journal of pharmacy and pharmaceutical sciences. 2009; 1(1): 145-150.
8. Ashish et al. Journal of drug delivery and Therapeutics. 2013; 3(3): 123-130
9. Suhas M, Kakade et al. Formulation and evaluation of mouth dissolving tablet of Losartan potassium. 2010; 1(3): 290-295.
10. Rameshwari S, Jeya Anandhi J, Formulation and Evaluation of Nifedipine sublingual tablet. 2009; 2(3): 44-48.
11. Mukesh G, Madhabai et al. AAPS Pharm sci. Tech. 2004; 5(3): 1-6.
12. Shailendra kumar S, Dinanath M, et al. fast disintegrating combination tablets of omeprazole and domeridone . 2009; 2(4): 54-62.
13. Kaushal P, Ashwini R, International journal of pharmtech research. 2012; 4(2): 715-724.
14. Jain CP, Naruka PS, Formulation and evaluation fast dissolving tablets of Valsartan. 2009; 1(1): 219-226.
15. Khatoon N,Rao Raghavendra G.N etal. Overview on fast dissolving oral films, International journal of chemistry and pharmaceutical science. 2013; 1(1):63-75.
16. Malviya R, Pranati S, et al. preparation and evaluation of disintegrating properties of maxima pulp power.2010; 2(1): 395-9.
17. Parashar B, Yadav V, et al. fast dissolving tablet , International journal of applied Pharmaceutics , 2012; 4(2): 17-22.
18. Nitin CM, Adhikar rao VY, Vaishali KG, Novel approaches in development of orodispersible tablets, J.pharm and Tech; 2(2): 283-286.
19. RS Masareddy, RV Kadia, FV Manvi, Development of mouth dissolving tablets of clozapine using two different techniques, 2004; 74(8): 526-528.

9. / Signatures of candidate / SIDDRAMAPPA
S10. / Remarks of Guide / Newer low costs directly compressible excipients will be cost effective in the development of orodispersible tablets of anti-allergic drugs have definite advantages in improving the patient compliance.
11. / Name and designation of
(in block letters)
11.1 / Guide / basawaraj bendegumble M .Pharm., (Ph. D)
lECTURER,
DEPT. OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES, GULBARGA -585-105.
11.2 / Signature
11.3 / Co-guide / Dr.M. v. RAMPURE M. Pharm., Ph.D.
Asst. professor,
DEPT. OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES, GULBARGA -585-105.
11.4 / Signature
11.5 / Head of the department / Dr.K.PURUSHOTAM.RAOM. Pharm., Ph.D.
Professor
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s MATOSHREE TARADEVI RAMPURE INSTITUTE OF PHARMACEUTICAL SCIENCES,
GULBARGA -585-105.
11.6 / Signature
12. / 12.1 / Remarks of Chairman and Principal
12.2 / Signature

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