Formulation and Evaluation of Fast Dissolving

“FORMULATION AND EVALUATION OF FAST DISSOLVING

TABLETS OF AN ANTIEMETIC DRUG”

DISSERTATION PROTOCOL

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

SATHYANARAYANA.N

I Year M. PHARM,

DEPARTMENT OF PHARMACEUTICS,

NARGUNDCOLLEGE OF PHARMACY,

BANGALORE- 85. KARNATAKA.

(2011-2012)

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA.

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR pg DISSERTATION

1. / Name of the Candidate & Address (In block letters) / SATHYANARAYANA.N
NARGUND COLLEGE OF PHARMACY,
DATTATREYANAGAR,2nd main,
100 ft ring road,BSK 3rd stage
BANGALORE-560085
2. / Name of the Institution / NARGUNDCOLLEGE OF PHARMACY,
DATTATREYA NAGAR,2ndmain,
100 ft ring road,BSK 3rd stage
BANGALORE-560085
3. / Course of Study and Subject / Master of pharmacy in
pharmaceutics
4. / Date of Admission to Course / 30th SEPTEMBER 2011
5. / Title of the Topic / “FORMULATION AND EVALUATIONOF
FAST DISSOLVING TABLETS OF AN
ANTIEMETIC DRUG”
6.
7.
8. / BRIEF SUMMARY OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
 Tablets are the most widely used dosage forms existing today because of its convenience in terms of self administration, compactness and ease in manufacturing. However, geriatric, pediatric and mentally ill patients experiencedifficulty in swallowing conventional tablets, leading to poor patient compliance. To overcome these problems, scientists have developed an innovative drug delivery system known asfastdissolving/disintegrating tablets (FDTs). These are novel types of tablets which dissolve/ disintegrate/ disperse in saliva with in few seconds without water.1
 According to European pharmacopoeia, 17theFDTs should dissolve/disintegrate in less than three minutes. The formulation is more useful for the bed-ridden patients and patients who have difficulty in swallowing. The benefits of FDTs are to improve patient’s compliance, rapid onset of action, increased bioavailability and good stability.
Fast dissolving tablets are also called as orodispersible tablets, mouth disintegrating tablets, orally disintegrating tablets, quick disintegrating tablets, fast dissolving tablets, rapid dissolving tablets, porous tablets, quick melt tablets and rapid melt tablets.
However, of all the above terms United States Pharmacopoeia (USP) 18approved the term ODT’s for these dosage forms. United States Food and Drug Administration (FDA) defined ODTs as “A solid dosage form containing medicinal substances or active ingredients which disintegrate rapidly within few seconds when placed up on the tongue”
Fast dissolving tablets are formulated mainly by two techniques. In one technique super disintegrants like crosscarmellose sodium, sodium starch glycolate and crospovidone are used. The other techniqueinvolves maximizing pore structure of the tablets by freeze drying and vacuum-drying.1
The objective of thework is to develop antiemetic fast dissolving tablets using different disintegrants which would disintegrate tablet rapidly in oral cavity.
Antiemetic drugsare used in the treatment of nausea, dizziness associated with motion sickness.
IDEAL FDT2s SHOULD
Allow high drug loading.
Require no water during oral administration as it dissolves/disintegrates in mouth within few seconds.
Have an acceptable taste.
Give a pleasant mouth feel.
Be less friable, but have good mechanical strength to withstand the post manufacturing.
Be stable in environmental conditions.
Leave least or no residue in mouth.
Be compatible with other ingredients.
PREPARATION TECHNIQUES OF FDT2

• Sublimation Method.
• Direct Compression Method.
• Phase Transition Process Method.
• Effervescent Agent Addition Method.
• Moulding Method.
• Spray Drying Method.
• Taste Masking Method.
• Freeze Drying or Lyophilization Method.

Salient Features of Fast Dissolving Drug Delivery System3
Administration in geriatric patients and psychiatric patients.
Convenience of administration and accurate dosing as compared to liquids.
No need of water to swallow the dosage formwhich is highly convenient feature for ease of administration to patients who refuse to swallow a tablet, such as pediatric and patients who are travelling and do not have immediate access to water.
Good mouth feel property of FDTshelps to change the basic view of medication as "bitter pill", particularly for pediatric patients.
Rapid dissolution of drug and absorption which may produce rapid onset of action.
Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down intothe stomach; in such cases bioavailability of drugs is increased.
Ability to provide advantages of liquid medication in the form of solid preparation.
Pre gastric absorption can result in improved bioavailability and it results in reduced dosage, improved clinical performance.
ADVANTAGES OF FDTs4
Administration to the patient with dysphagia (difficulty in swallowing)such as the elderly stroke victims, bedridden patient , patients affected by renal failure and patients who refuse to swallow such as pediatric, geriatric & psychiatric patients.
Achieve increased bioavailability/rapid absorption through pregastric absorption of drug from mouth, pharynx &oesophagus as saliva passes down.
Rapid drug therapy intervention.
Convenient for administration and provides patient compliance for disabled, bedridden patient and for travellers and busy people, who do not always have access to water.
Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients.
The risk of choking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety.
6.2 REVIEW OF LITERATURE

• Swamivelmanickam et al., improved patient complianceby designing an oral drug delivery system which remains the preferred route of drug delivery inspite of various disadvantages. They formulated “mouth dissolving tablets” (MDTs) which disintegrate or dissolve rapidly without waterwithin few seconds in the mouth due to the action of superdisintegrants or maximizing pore structure in the formulation. Mouth dissolving tablets were found to be advantageous particularly for pediatric, geriatric and mentally ill patients who have difficulty in swallowing conventional tablets and capsules.1

• Shobhit Kumar et al.,have suggested in their review article thatby better understanding of biochemical andPhysicochemicalproperties related to the drug action. Fast dissolving tablets (FDTs)havebecome popular due to better patient compliance and are preferred over conventional capsulesandtablets. RecentFDTproduction techniques havehelped inmanagement of convenientdosing in patients suffering with dysphagia.Anoverview of desiredcharacteristics, preparation techniquesandpatented technologiesof FDTs formulation are extensively reviewed in this article.2

• Bankim Chandra Nandy et al., have elaborated on the problems faced by geriatric and pediatric patients which leads to poor patient compliance due to unpalatable taste of drug. A number of fast-dissolving formulations are in market like Claritin Reditab (Manufacturer R.P.Scherr, Inc.), Risperdal M-Tab (Manufacturer Janseen pharmaceutics.), Tempra Quicklets(Manufacturer Cima Labs, inc) and the technology is still improving. The conventional tablet seems to be most popular because of its ease of transportability and comparatively low manufacturing cost but poor patient compliance in case of pediatrics and geriatrics patients. In response to this, mouth dissolving drug delivery system (MDDs) was developed as an alternative to tablets, capsules & syrups. A variety of MDDs like mouth dissolving tablets and mouth dissolving films (MDFs) were commercialized. MDFs evolved over the past few years from the confection and oral care market in the form of breath strips & became a novel & widely accepted form by consumers.3
• Deshmukh Keshav Ram et al., reviewed the information about mouth dissolving tablets prepared by solid dispersion technique. Mouth dissolving tablets are being increasingly recognized in the market because of their potential benefits over conventional tablets. Solid dispersion is an innovative technique to improve solubility of drug moieties with low solubility profile. Formulation of solid dispersion as mouth dissolving tablets not only improves dissolution characteristics of drug but also provides easy administration and quicker action. Various techniques used for the preparation of mouth dissolving tablet and solid dispersion are described in article. Furthermore, the various characterization parameters used for mouth dissolving tablets formulated by solid dispersion technique are discussed.4

• Seong Hoon Jeong et al., have prepared FDTs by several methods including crystalline transition, phase transition, sublimation, spray drying and direct compression.Of these approaches,a conventional tablet compression method is used most widely because of its low cost and ease ofmanufacturing. Research on FDTs prepared by the compression method has focused on decreasing thedissolution (or disintegration) time of the tablets in the mouth, while maintaining sufficiently high mechanicalstrength to withstand handling during manufacturing, packaging, and transportation. The key to developing a successful FDT formulation by the compression method is to select the right excipients and the right processing techniques. In general,FDTs are made of highly hydrophilicmaterials and possess highly porous structures forfast water absorption into the tablet matrix. Theexcipients that are currently used as wellas those that are expected to be used for the futuredevelopment of improved FDTs are described.5

• Yourong Fu et al., have elaborated on the ever-increasing demand for FDTs in the lastdecade, and the field has become a rapidly growing area in the pharmaceuticalindustry. Uponintroduction into the mouth, these tablets dissolve or disintegrate in themouth inthe absenceofadditional water for easy administration of active pharmaceuticalingredients. Thepopularityand usefulness of the formulation resulted in development ofseveral FDT technologies. The review describes various formulations and technologiesdevelopedto achieve fastdissolution/dispersion of tablets in the oral cavity. In particular, thisreview describes in detailFDT technologies based on lyophilization, molding, sublimation,and compaction, as well asapproaches to enhancing the FDT properties, suchas spray drying,moisture treatment,sintering, and use of sugar-based disintegrants. In addition,taste-masking technologies,experimental measurements of disintegration times,and clinicalstudies are also discussed.6

• Kamal Saroha et al., in their review, have described the improved palatability in orally administered products thathas prompted thedevelopment of numerous formulations with improved performance and acceptability. OrallyDisintegrating tablets (ODTs) have received ever-increasing demand during the last fewdecades,and the field has become a rapidly growing area in the pharmaceutical industry. Theuniqueproperty of mouth dissolving tablet is that they are rapidly disintegrating and/ordissolving andrelease the drug as soon as they come in contact with saliva, thus obviate the requirement ofwater during administration. This article reviews the earlier applications andmethodologies oftaste masking and also emphasize on the recent developments and approachesof bitternessreduction for orally used pharmaceuticals. Apart from the conventional methods offabrication. This review also provides the detailed concept of some unique patents; technologiesdevelopedandmarketed formulations of Mouth Dissolving Tablets (MDTs).7

• Goyani Sandip M et al.,formulated meclizine HCl as fast disintegrating tablets using different disintegrants which would disintegrate tablets rapidly in oral cavity. Nine batches of meclizine HCl orally disintegrating tablet were prepared by direct compression method using sodium starch glycolate, crosscarmellose sodium, crospovidone as disintegrant in different concentrations in order to achieve faster disintegration of the tablets. The influence of the disintegrant concentration on the release of meclizine HCl was studied. The formulated batches were characterized by different physical parameters. Physical parameters of all formulated tablets were within acceptable limits. The study revealed that the formulation containing crospovidone as disintegrants showed faster disintegration compared to others.8

• Gamal M.Mahrous et al.,prepared and developed ODTs of Meclizine (MZ HCl) withsufficient mechanical integrity, content uniformity, and acceptable palatability to assist patientsof any age for easy administration. Meclizine HCl is an anti-emetic drug used for managementof dyspepsia, heartburn, epigastric pain, nausea, and vomiting. The interaction of meclizine andused excipients was studied using differential scanning calorimetry (DSC). The ODTs wereprepared by direct compression method. The effect of varying concentrations of differentsuperdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolateondisintegration time and dissolution rate was studied. The prepared tablets were evaluatedfor hardness, friability, and disintegration time and in-vitro drug release. DSC studies revealed thatno interaction between the drug and the used excipients. All tablets had hardness in the range4.2 5.6kp and friability less than 1%. Weight variation and drug content of all formulation werewithinofficial limits according to BP. In-vitro drug release study of ODTs showedthat more than90% of the drug was released within 10 min. Palatability test by 12 volunteersshowedacceptabletaste and mouth feels. Thus, results obtained conclusively demonstratedsuccessfulrapiddisintegration of the formulated tablets and acceptable palatability.9

• Gupta M.M et al., investigated use of tablets for motion sickness during repeated motion such as from the swell of the sea, the movement of a car, the motion of a plane in turbulent air, etc. Most medications for motion sickness need to be taken at least 30 minutes prior exposure to the activity that can cause the problem. These dosage forms would be preferred by pediatric and geriatric patients since these are not associated with fear of choking. Meclizine HCl, a poorly water soluble and bitter drug could be successfully incorporated in the fast dissolving films with the help of solubilizers such as β-Cyclodextrin and PEG-400.10

• Reshu Gupta et al., has formulated fast dissolving tablets of midazolam hydrochloride(MH), an antiemetic drug. Fast disintegrating tablets (FDT) of midazolam hydrochloride were preparedwith the addition of different superdisintegrants like Kollidon CL, AcDiSol SD711 and Glycolys. Each ofthese superdisintegrants were used in concentrations of 2- 4% w/w. Formulation with 3% w/w KollidonCL showed minimum disintegration time (<20 seconds). Furthermore, increasing the concentration of thesuperdisintegrants did not decrease the disintegration time (DT) significantly. The excipients usedfor this study was based on the compatibility studies. All the formulations were prepared by directcompression method. Among all the formulations Kollidon CL at 2.4 mg/tablet gives 99.65% drug releasein 10 min. by spectroscopic method. It was considered as optimized batch. The optimized batch passed all the evaluation parameters and stability studies.11

• H.A.Patel et al., developed and characterized fast dissolving tablets of Domperidone using direct compression and wet granulation technique. In this method the different excipients used were microcrystalline cellulose, Cross caramellose sodium, Cross povidone, Sodium starch glycolate, Magnesium Stearate, Talc etc. Pre compression and post compression parameters were evaluated for all the ten formulations (D1-D10). In vitro drug release showed that the drug releasedwas almost in the range of 94-97% in 10 minutes. By comparing cumulative drug release, in vitro disintegration time and wetting time, it was found that direct compression method was better than wet granulation method. Depending upon cumulative drug release, in vitro disintegration time, and wetting time resultsformulation D1 was selected for stability studies and subjected to stability studies at 25oC,30oC and 40oCfor 2 months. Overall, formulation D1 formulated by direct compression was found to be the best formulation.12

• Mohd Azharuddin et al., formulated and evaluated fast disintegrating tablets ofGranisetron HCl using natural polymers. Tablets were prepared by direct compression method using different drug polymer concentrations. Fourier Transform Infrared Spectroscopy (FT-IR) study revealed no chemical interaction between drug and polymers used. Precompression and postcompression parameters were within the pharmacopoeia limits. Disintegration and dissolution data of tablets were directly proportional to the superdisintegrants concentration. Selected fast dissolving tabletF8 containing plantago ovate 5%w/w has released 99.66 % within 3min.13

• Ibrahim S Khattab et al., preparedhyoscine butylbromide (a drug with bitter taste) tablets that can rapidly disintegrate in saliva. The granules were prepared by the extrusion method using aminoalkyl methacrylate copolymers (EudragitE-100). The drug dissolved rapidly in medium atpH 1.2 in a dissolution test while none of the drugs dissolved from the granules (% of dissolved <5%) even after 8 h at pH 6.8. Rapidly disintegrating tablets were prepared using taste-masked granules and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102)and low substituted hydroxypropylcellulose (L-HPC, LH-11). The granules and excipients weremixed well (mixing ratio by weight, crystalline cellulose: L-HPC, was 8:2) with 1% magnesiumstearate as a lubricant and subsequently compressed at 500-1,500 kgf in a single-punch tabletingmachine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules havesignificant strength (crushing strength was 3.5 kg), and a rapid disintegration time (within 30sec) was observed in the saliva of healthy volunteers. None of the volunteers sensed any bittertaste after the disintegration of the tablet that contained the taste-masked granules. The resultsconfirmed that rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients that are commonly used in tablet preparation.14

• Parmar R.B. et al.,developed fast dissolving tablets of domperidone by direct compression method using Avicel PH 102 and Sodium Starch Glycolate as diluents and superdisintegrants respectively. Allformulations were evaluated for characteristics such as hardness, friability, disintegration timeand Dissolution rate. An effective, pleasant tasting formulation was found to have a goodhardness of 3 kg/cm2, disintegration time of 27±1 seconds and in vitro drug release of not lessthan 95% within 30 minutes. The drug release was found to be comparable with the marketeddispersible tablet.15

• Sharma Shailesh et al., developed mouth dissolving tablets of domperidone. Tablets containing domperidone, camphor and crospovidone were prepared by direct compression technique. The tablets should be prepared using an optimum concentration of camphor and a higher percentage of crospovidone. A contour plot was also presented to graphically represent the effect of the independent variables on the disintegration time 40 s and percent friability 0.6%. A checkpoint batch was also prepared to prove the validity of the evolved mathematical model.16

6.3 OBJECTIVES OF THE STUDY:
In the present study an attempt will be made to prepare and formulate oro dispersible tablets to check theeffect of super disintegrants on the release profile of the drug from the tablet.
Screening of excipients for compatibility and efficacy for developing the formulation.
Selection of suitable super disintegrants to develop the dosage form based on physicochemical
properties of drug and excipients.
Selection of suitable technology for preparing fast dissolving tablets.