INTRODUCTION

Oral routes of drug administration have wide acceptance up to 50-60% of

total dosage forms. Solid dosage forms are popular because of ease of
administration, accurate dosage, self-medication, Pain avoidance and most
importantly the patient compliance. The most popular solid Dosage forms are
being tablets and capsules; one important drawback of this dosage forms for some
patients, is the difficulty to swallow. Drinking water plays an important role in
the Swallowing of oral dosage forms. Often times people experience
inconvenience in swallowing conventional dosage forms such as tablet when
water is not available, in the case of the motion sickness (kinetosis) and sudden
episodes of coughing during the common cold, allergic condition and bronchitis.
For this reason, tablets that can rapidly dissolve or disintegrate in the oral cavity
have attracted a great deal of attention. Dispersible tablets are not only indicated
for people who have swallowing difficulties, but also are ideal for active people.[1]

Immediate release tablets are also called as mouth-dissolving tablets,

melt-in mouth tablets, Oro-dispersible tablets, rapid melts, porous tablets, quick
dissolving etc. Immediate release tablets are those when put on tongue
disintegrate instantaneously releasing the drug which dissolve or disperses in the
saliva. Some drugs are absorbed from the mouth, pharynx and esophagus as the
saliva passes down into the stomach. In such cases, bioavailability of drug is
significantly greater than those observed from conventional tablets dosage form.
The advantage of mouth dissolving dosage forms are increasingly being
recognized in both, industry and academics. Their growing importance was
underlined recently when European pharmacopoeia adopted the term “or
dispersible tablet” as a tablet that to be placed in the mouth where it disperses
rapidly before swallowing. According to European pharmacopoeia, the ODT

1
should disperse/disintegrate in less than three minutes. The basic approach in
development of FDT is the use of super disintegrants like cross linked
carboxymethyl cellulose (Crosscarmellose), sodium starch glycolate (primo gel,
explotab), polyvinylpyrollidone (Polyplasdone) etc, which provide instantaneous
disintegration of tablet after putting on tongue, their by release the drug in saliva.
The bioavailability of some drugs may be increased due to absorption of drug in
oral cavity and also due to pregastric absorption of saliva containing dispersed
drugs that pass down into the stomach. More ever, the amount of drug that is
subjected to first pass metabolism is reduced as compared to standard tablet. The
technologies used for manufacturing fast-dissolving tablets are freeze-drying,
spray-drying, tablet molding, sublimation, sugar-based excipients, tablet
compression, and disintegration addition. As a result of increased life expectancy,
the elderly constitute a large portion of the worldwide population today. These
people eventually will experience deterioration of their physiological and
physical abilities.[2]

CRITERIA FOR FAST DISSOLVING DRUG DELIVERY SYSTEM:

The tablets should

1. Be compatible with taste masking.
2. Be portable without fragility concern.
3. Have a pleasant mouth feel.
4. Leave minimum or no residue in the mouth after oral administration.
5. Exhibit low sensitive to environmental condition as temperature and humidity.
6. Allow the manufacture of the tablet using conventional processing and
packaging
7. Equipments at low cost.

2
Salient Feature of Fast Dissolving Drug Delivery System:

1. Ease of Administration to the patient who cannot swallow, such as the elderly,
stroke victims, bedridden patients, patient affected by renal failure and patient
who refuse to swallow such as pediatric, geriatric & psychiatric patients.
2. 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.
3. Rapid dissolution and absorption of the drug, which will produce quick onset
of action. Some drugs are absorbed from the mouth, pharynx and esophagus
as the saliva passes down into the stomach. In such cases bioavailability of
drug is increased.
4. Pre gastric absorption can result in improved bioavailability and as a result of
reduced dosage; improve clinical performance through a reduction of
unwanted effects.
5. Good mouth feel property helps to change the perception of medication as
bitter pill particularly in pediatric patient.
6. The risk of chocking or suffocation during oral administration of conventional
formulation due to physical obstruction is avoided, thus providing improved
safety.
7. New business opportunity like product differentiation, product promotion,
patent extensions and life cycle management.
8. Beneficial in cases such as motion sickness, sudden episodes of allergic attack
or Coughing, where an ultra-rapid onset of action required.
9. An increased bioavailability, particularly in cases of insoluble and
hydrophobic drugs, due to rapid disintegration and dissolution of these tablets.
10. Stability for longer duration of time, since the drug remains in solid dosage
form till it is consumed. So, it combines advantage of solid dosage form in
terms of stability and liquid dosage form in terms of bioavailability.[3]

3
ADVANTAGES OF FAST DISSOLVING TABLETS
1. Administered without water, anywhere, any time. Suitability for geriatric and
pediatric patients, who experience difficulties in swallowing and for the other
groups that may experience problems using conventional oral dosage form,
due to being mentally ill, the developmentally disable and the patients who
are un-cooperative, or are on reduced liquid intake plans or are nauseated.
2. Beneficial in cases such as motion sickness, suede episodes of allergic attack
or coughing, where an ultra rapid onset of action required.
3. An increased bioavailability, particularly in cases of insoluble and
hydrophobic drugs, due to rapid disintegration and dissolution of these
tablets.
4. Stability for longer duration of time, since the drug remains in solid dosage
form till it is consumed. So, it combines advantage of solid dosage form in
terms of stability and liquid dosage form in terms of bioavailability.

LIMITATIONS OF MOUTH DISSOLVING TABLETS

1. The tablets usually have insufficient mechanical strength. Hence, careful
handling is required during manufacturing process.
2. The tablets may leave unpleasant taste and/or grittiness in oral cavity if not
formulated properly.
3. Drugs with larger doses are difficult to formulate into FDT e.g., rifampin (600
mg), ethambutol (1000mg) etc.

IDEAL REQUIREMENTS

❖ No bitter taste, dose less than 20mg.

❖ Small to moderate molecular weight.
❖ Good solubility in water and saliva.

4
TECHNIQUES FOR PREPARING FAST DISSOLVING
TABLETS

Many techniques have been reported for the formulation of immediate release
tablets

1. Freeze drying / lyophilization

2. Tablet Molding

3. Spray drying

4. Sublimation

5. Direct compression

6. Mass extrusion
1. Freeze-Drying or Lyophilization

Freeze drying is the process in which water is sublimed from the

product after it is frozen. This technique creates an amorphous porous structure
that can dissolve rapidly. The active drug is dissolved or dispersed in an aqueous
solution of a carrier/polymer. The mixture is done by weight and poured in the
walls of the preformed blister packs. The trays holding the blister packs are passed
through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion.
Then the frozen blister packs are placed in refrigerated cabinets to continue the
freeze-drying. After freeze-drying the aluminum foil backing is applied on a
blister-sealing machine. Finally, the blisters are packaged and shipped. The
freeze-drying technique has demonstrated improved absorption and increase in

5
bioavailability. The major disadvantages of lyophilization technique are that it is
expensive and time consuming; fragility makes conventional packaging
unsuitable for these products and poor stability under stressed conditions.

2. Tablet Molding:

Molding process is of two types’ i.e., solvent method and heat

method. Solvent method involves moistening the powder blend with a hydro
alcoholic solvent followed by compression at low pressures in molded plates to
form a wetted mass (compression molding). The solvent is then removed by air-
drying. The tablets manufactured in this manner are less compact than
compressed tablets and posses a porous structure that hastens dissolution. The
heat molding process involves preparation of a suspension that contains a drug,
agar and sugar (e.g., mannitol or lactose) and pouring the suspension in the blister
packaging wells, solidifying the agar at the room temperature to form a jelly and
drying at 30°C under vacuum. The mechanical strength of molded tablets is a
matter of great concern. Binding agents, which increase the mechanical strength
of the tablets, need to be incorporated. Taste masking is an added problem to this
technology. The taste masked drug particles were prepared by spray congealing
a molten mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin,
polyethylene glycol and an active ingredient into a lactose-based tablet triturate
form. Compared to the lyophilization technique, tablets produced by the molding
technique are easier to scale up for industrial manufacture.

3. Spray Drying:

In this technique, gelatin can be used as a supporting agent and as a

matrix, mannitol as a bulking agent and sodium starch glycolate or
Crosscarmellose or Crosspovidone are used as superdisintegrant. Tablets

6
manufactured from the spray-dried powder have been reported to disintegrate in
less than 20 seconds in aqueous medium. The formulation contained bulking
agent like mannitol and lactose, a superdisintegrant like sodium starch glycolate
& Crosscarmellose sodium and acidic ingredient (citric acid) and/or alkaline
ingredients (e.g., sodium bicarbonate). This spray-dried powder, which
compressed into tablets showed rapid disintegration and enhanced dissolution.

4. Sublimation:

To generate a porous matrix, volatile ingredients are incorporated in

the formulation that is later subjected to a process of sublimation. Highly volatile
ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid,
camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed
along with other excipients into a tablet. This volatile material is then removed
by sublimation leaving behind a highly porous matrix. Tablets manufactured by
this technique have reported to usually disintegrate in 10-20 sec. Even solvents
like cyclohexane; benzene can be used as pore forming agents.

5. Direct Compression:

Direct compression represents the simplest and most cost-effective

tablet manufacturing technique. This technique can now be applied to preparation
of ODT because of the availability of improved excipients especially super
disintegrants and sugar -based excipients.

(a) Superdisintegrants: In many orally disintegrating tablet technologies based

on direct compression, the addition of superdisintegrants principally affects the
rate of disintegration and hence the dissolution. The presence of other formulation
ingredients such as water-soluble excipients and effervescent agents further

7
hastens the process of disintegration.

(b) Sugar Based Excipients: This is another approach to manufacture ODT by

direct compression. The use of sugar-based excipients especially bulking agents
like dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol, sorbitol,
starch hydrolysate, polydextrose and xylitol, which display high aqueous
solubility and sweetness, and hence impart taste masking property and a pleasing
mouth feel. Mizumito et al have classified sugar-based excipients into two types
on the basis of molding and dissolution rate.

6. Mass-Extrusion:
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 test masking.[4]

8
PATENTED TECHNOLOGY FOR FAST DISSOLVING
TABLETS
1.Zydis Technology:

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 and resilience 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
manufacturing process to ensure production of porous units to achieve rapid
disintegration while 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 units during freeze-drying process or long-term
storage. Zydis products are packed in blister packs to protect the formulation from
moisture in the environment.
1.Durasolv Technology:

Durasolv is the patented technology of CIMA labs. The tablets made

by this technology consist of drug, filler and a lubricant. Tablets are prepared by
using conventional tabletting equipment and have good rigidity. These can be
packaged into conventional packaging system like blisters. Durasolv is an
appropriate technology for product requiring low amounts of active ingredients.

9
2.Orasolv Technology:

CIMA labs have developed Orasolv Technology. In this system

active medicament is taste masked. It also contains effervescent disintegrating
agent. 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.
3.Flash Dose Technology:

Flash dose technology has been patented by fuisz. Nurofen meltlet, a new
form of ibuprofen as melt in mouth tablets prepared using flash dose technology
is the first commercial product launched by Biovail Corporation. Flash dose
tablets consist of self-binding shear form matrix termed as “floss”. Shear form
matrices are prepared by flash heat processing.

4. Wow tab Technology:

Wow tab technology is patented by Yamanouchi Pharmaceutical Co. WOW

means “Without Water”. In this process, combination of low mould ability
saccharides and high mould ability saccharides is used to obtain a rapidly melting
strong tablet. The active ingredient is mixed with a low mould ability saccharide
(e.g., lactose, glucose, and mannitol) and granulated with a high mould ability
saccharide (e.g., Maltose, oligosaccharides) and compressed into tablet.

5. Flash tab Technology:

Tablet prepared by this system consists of an active ingredient in the form of

micro crystals. Drug micro granules may be prepared by using the conventional
techniques like Coacervation, micro encapsulation and extrusion spheronisation.
All the processing utilized conventional tabletting technology

10
MECHANISM OF SUPERDISINTEGRANTS

There are four major mechanisms for tablets disintegration as follows

1. Swelling:

Perhaps the most widely accepted general mechanism of action for tablet
disintegration is swelling. Tablets with high porosity show poor disintegration
due to lack of adequate swelling force. On the other hand, sufficient swelling
force is exerted in the tablet with low porosity. It is worthwhile to note that if the
packing fraction is very high, fluid is unable to penetrate in the tablet and
disintegration is again slows down.

2. Porosity and capillary action (Wicking):

Disintegration by capillary action is always the first step. When we put the
tablet into suitable aqueous medium, the medium penetrates into the tablet and
replaces the air adsorbed on the particles, which weakens the intermolecular bond
and breaks the tablet into fine particles. Water uptake by tablet depends upon
hydrophilicity of the drug /excipients and on tableting conditions. For these types
of disintegrants maintenance of porous structure and low interfacial tension
towards aqueous fluid is necessary which helps in disintegration by creating a
hydrophilic network around the drug particles.

3. Due to disintegrating particle/particle repulsive forces

Another mechanism of disintegrate attempts to explain the swelling of

tablet made with ‘non-swellable’disintegrants. Guyot-Hermann has proposed a
particle repulsion theory based on the observation that non-swelling particle also
cause disintegration of tablets. The electric repulsive forces between particles are
the mechanism of disintegration and water is required for it. Researchers found
that repulsion is secondary to wicking.

11
4. Due to deformation

During tablet compression, disintegrated particles get deformed and these

deformed particles get into their normal structure when they come in contact with
aqueous media or water. Occasionally, the swelling capacity of starch was
improved when granules were extensively deformed during compression. This
increase in size of the deformed particles produces a breakup of the tablet. This
may be a mechanism of starch and has only recently begun to be studied.[5]

12
 LITERATURE REVIEW
S.Khailkhura. et. al., Developed a orally dispersive tablets are solid dosage
forms that dissolve in the mouth in within 10 to 30 seconds, enabling waterless
ingestion. The tablet dissolves quickly due to its fast breakdown, which also
causes the effects to start acting quickly. ODTs can help patients with a variety
of conditions, including pediatrics, geriatrics, psychosis, dysphagia, bedridden
discomfort, comatose patients, young patients with undeveloped muscular and
nervous systems, patients with hand tremors, and patients who travel often. It
provides high stability, precise dosage, efficient manufacture, and smaller
packing: self-administration is allowed on long journeys because water is not
required. ODTS are a cost-effective way to distribute drugs. When a medicine is
absorbed through the buccal cavity, ODTs constitute a critical drug delivery
method. Spray drying. sublimation, and other scientific procedures like freeze
drying, moulding, and direct compression. The availability of ODTs as over-the-
counter drugs for the treatment of a range of illnesses is increasing. This article's
objective is to go over the benefits, drawbacks, formulation difficulties,
manufacturing methods, patented technologies. commercially available
formulations, and evaluation checks of ODT. The word "Oro dispersible tablets"
was created by the European Pharmacopoeia. This is an uncoated tablet that
dissolves easily in the mouth for 3 minutes before being swallowed.

P.M. Ghourichayet. al., were performing orally disintegrating tablets (ODTS)

rapidly disintegrate or dissolve in the oral cavity without using water. Demand
for ODTs has increased, and the field has overgrown in the pharmaceutical
industry and academia. It is reported that ODTs have several advantages over
other conventional tablets. Since some of them are absorbed from the mouth,
pharynx, and esophagus as the saliva passes down into the stomach, in such cases,
the bioavailability of the drug improves meaningfully. Furthermore, the
immediate release property of ODTs makes them a popular oral dosage form in

13
patients with swallowing challenges, children, and for cases with a need for rapid
onset of action. The current review article explains the features of active
ingredients and excipients used in the formulation of ODTs, discusses multiple
ODT formulation and preparation techniques with their merits and demerits, and
also, offers remedies for problems associated with ODTs. Moreover, quality
control steps and required considerations are presented 171

Geethalakshmi et.al., Formulated and evaluated of fast dissolving tablets of

Metoclopramide hydrochloride (MH) a potent antiemetic and is effective in the
treatment of nausea and vomiting associated with cancer chemotherapy,
pregnancy, migraine etc. It is also used for the treatment of diabetic gastric stasis
and gastro-oesophageal reflux disease. The fast-dissolving tablet was prepared by
using different superdisintegrant with different ratio. FT-IR study revealed no
interaction between the drug and excipients. Tablets were characterized for
hardness, friability, weight variation, wetting time, disintegration time, drug
content, and dissolution and dispersion time. Among the nine formulations, F6
was selected as the best formulation as its wetting time was 39 seconds,
disintegration time was 12 seconds, dispersion time was 49 seconds and %CDR
after 6 minutes was 99.46%. F6 was found to be stable at 40 °C ± 2 °C and 75 ±
5 % RH which was confirmed by FT-IR study.

Deshmukh et.al., reported that Sildenafil citrate is a pharmacological agent

which has proven useful in treatment of erectile dysfunction, pulmonary arterial
hypertension as well as high altitude motion sickness. Sildenafil citrate exhibits
an absolute bioavaibality of about 40% and is reported to result in maximum
observed plasma concentration of about 30-120 minutes following after oral
administration. Sildenafil citrate exhibits low water solubility, namely 3.5mg/ml.
This low water solubility with its high presystemic metabolism have contributed
to its low oral bioavailability. Thus, there is a need to to improve the
bioavailability of sildenafil citrate. Fast dissolving tablet of sildenafil citrate were

14
prepared with an intention to gain pre gastric absorption that will eliminate the
presystemic metabolism of drug. Attempts were also made to improve the
aqueous solubility of the drug by forming its nanocrystals. The nanocrystals of
sildenafil citrate were formed by nanoprecipitation technique and were evaluated
for particle size and shape by scanning electron microscopy and were also
subjected to DSC and FTIR analysis. These formed nanocrystals were further
considered as API for the fast-dissolving tablet. The formulated F3 formulation
(fast dissolving tablet containing cross povidone as polymer and sildenafil citrate
nanocrystals) shows rapid drug release within 2 minutes as compared to the tablet
containing pure drug.

B.S. Patil et.al., Developed fast dissolving tablet (FDTs) of Candesartan

cilexetil by sublimation technique using camphor as subliming agent together
with croscarmellose sodium and crospovidone as superdisintegrants. The
prepared formulations were evaluated for pre-compressional and post-
compressional parameters. The compatibility of drug with other ingredients was
checked by FTIR studies, the results revealed that there was no interaction
between dug and other excipients. The values of pre-compressional parameters
were within prescribed limits and indicated good free flowing properties. In all
the formulations the hardness test indicates good mechanical strength. Friability
of all formulations was less than 1. Drug content was found to be high (≥
101.02%) and uniform in all the formulations. The tablet thickness was found to
be 3.10 to 3.16 mm. The weight variation results revealed that average percentage
deviation was less then ± 7.5 %, which provides good uniformity in all
formulations. The disintegration time of the tablets found to be in the range of 21
to 40 sec. The formulations CCC4, CCU4,50 % of drug released in 1.02, 2.42
min, and 90 % of drug released in 3.37, 6.19 min. Stability study carried out as
per ICH guidelines for three months and results revealed that upon storage
disintegration time of tablets decreased significantly (p<0.05).

15
B.G. Prajapati et.al., Prepared fast dissolving tablets of Domperidone by wet
granulation. In the present research study, Sodium Starch Glycolate, was taken as
super disintegrant and starch paste as a binder for the study. Here the
Domperidone (anti-emetic) is taken as the model drug for the study and wet
granulation as a method for preparation of the Fast- Dissolving Tablet. The
disintegrant incorporated during the wet granulation process as extra granular
incorporation. A 32 full factorial design was applied to investigate the combine
effect of 2 formulation variable: Superdisintegrants and starch paste. Here the
concentration of Superdisintegrants and concentration of starch paste were taken
as independent variable, X1 and X2 respectively. The effect of Disintegration
time, wetting time, Q30 and friability were investigated as dependent parameters.
The optimized batch obtained from the factorial design was compared with the
marketed product. The stability study of the optimized batch is also done at 40 oC
and 75%RH.

D.P Deshmukh et.al., reviewed and reported that, Tablet is the most popular
among all oral dosage forms existing today because of recently .fast-dissolving
drug delivery system have started gaining popularity and acceteptance as new
drug delivery systems because they are easy to administer and lead to better
patient compliance its convenience of self administration, compactness and easy
manufacturing; however hand tremors; dysphasia in case of geriatric patients, the
under developed patients, the problem of swallowing is common phenomena
which leads to poor patients compliance . To overcome these drawbacks, mouth
dissolving tablets (MDT) or orally disintegrating tablets ;( ODT) has immersed
as alternative oral dosage forms. These are novel types; of tablets that
disintegrate/dissolve/disperse in saliva within few seconds. According to
European Pharmacopoeia, the ODT should disperse/disintegrate in less than three
minutes. The basic approach used in development of MDT is the use of
superdisintegrants like Cross linked carboxymethyl cellulose, sodium starch

16
glycolate. PVP etc. which provides instantiations disintegration of tablet after
putting on tongue, there by releasing the drug in saliva. The bioavailability of
some drugs may be increased due to absorption of drugs in oral cavity and also
due to pregastric absorption of saliva containing dispersed drugs that pass down
in to the stomach. Moreover, the amount of drug i.e., subject to first pass
metabolism is reduced compared to the standard tablets.

H.S. Sunitha et.al., Formulated and evaluated taste masked fast disintegrating
tablets of Captopril to increase the palatability and bioavailability of the drug.
Fast disintegrating tablets of Captopril were prepared by direct compression
method using β-cyclodextrin as a complexing agent to mask the bitter taste of
Captopril. Guar gum as natural super disintegrants was used in different
concentration 2.5 mg, 5 mg, 7.5 mg, 10 mg respectively. The Captopril - β-
cyclodextrin complex were characterized by FT-IR, DSC and XRD.
Compatibility studies by FT-IR showed no significant interactions between drug
and excipients. DSC and XRD analysis confirmed the formation of complex for
taste masking. The developed tablet formulations were evaluated for pre
compression and post compression parameters which complied official limits.
Among all the formulations, formulation F4 containing guar gum 10 mg gives
best disintegration and dissolution profile compared with other formulations,
showed drug release of 99.86±0.54 % with 12 min and disintegration time
50.16±1.32 sec. From this study we concluded that the formulated tablets of
Captopril containing guar gum of concentration 10 mg was better and effective
than conventional tablets to meet patient compliance along with fast relief from
hypertension.

Suhas M. Kakade et.al., Orally disintegrating tablets are gaining popularity over
conventional tablets due to their convenience in administration and suitability for
patients. The purpose of this research was to mask the intensely bitter taste of
tramadol hydrochloride and to prepare orally disintegrating tablets for

17
achievement of quick onset of action of the drug. Tramadol hydrochloride is an
analgesic which has been proved to be efficient in managing relief from pain and
including pain after surgery. In the present study an attempt has been made to
prepare bitter less orally disintegrating tablet of Tramadol Hydrochloride using
Eudragit E 100 as a taste masking agent. Mass extrusion was the technique used
for preparing taste masked granules and tablet was prepared with using super-
disintegrants like cross-povidone, croscarmellose sodium and sodium starch
glycolate, were prepared blend and evaluated for the pre-compression parameters
such as bulk density, compressibility, angle of repose etc. The prepared batches
of tablets were evaluated for hardness, weight variation, friability, drug content,
disintegration time and in-vitro dissolution profile and found satisfactory. Among
the formulations containing Cross-povidone was least and tablets showed fastest
disintegration. The drug release from orally disintegrating tablets increased with
increasing concentration of super-disintegrants and was found to be highest with
formulations containing Cross-povidone. Thus, results conclusively
demonstrated successful masking of taste and fastest disintegration of the
formulated tablets in oral cavity.

Raval S.B et.al., Tramadol is an Opioid pain-killer. It is bitter in taste. In the

present study an attempt has been made to prepare bitter less mouth dissolving
tablets of Tramadol hydrochloride using ion exchange resin Indion 294 as a taste
masking agent. Ion exchange resonates and tasteless granules were prepared with
Indion 294 in weight ratio of 1:2. Prepared complex was further examined
through U.V. Visible Spectroscopy. The mouth dissolving tablets of both
resonates and granules were prepared with different superdisintegrants e.g., cross
carmallose sodium, crosspovidone & Indion 234 in different concentration. The
blend was examined for their flow properties. The tablets were evaluated for
physiochemical properties. The tasteless blends having good flow properties. The
prepared zero-defect mouth dissolving tablets were passed all the official and

18
non-official parameters. The disintegration time was also tested and was found to
be less than one minute. A tablet having resonates shows less time for onset of
action of drug due to enhanced and fast release of Tramadol hydrochloride. It was
concluded that tablets prepared by addition of super disintegrant Indion 234 has
less disintegration time, fast and more dug release than those prepared by
crosspovidone.

19
 DRUG PROFILE
Drug name
Torsemide

Synonyms

• Torasemidum (Latin)
• Torasemide (Spanish)

Categories

• Anti hypertensive agents

• Diuretics

Structural Formula

Chemical name
1-{4-[(3 methyl phenyl ) Amino] pyridine -3-sulfonyl}-3-(propan-2-
yl) urea.

20
 Molecular Formula

C16H20N4O3S
Description
Nature : White to off white crystalline powder.
Solubility : Soluble in Methanol , slightly soluble in water.
Melting point : 164oc
pka : 7.1
Molecular weight
348.43gm/ml
Mechanism of Action:
It inhibits reabsorption of sodium and chloride in the ascending loop of
henle and distal renal tubule, interfering with the chloride-binding co-
transport system, thus causing increased excretion of water, sodium,
chloride, magnesium and calcium. It does not alter glomerular filtration
rate, renal plasma flow, or acid-base balance. Pharmacokinetics
Absorption Bioavailability is approximately 80% Volume of
distribution The volume of distribution of torsemide is 12 liters to 15
liters in normal adults or in patients with mild to moderate renal failure
or congestive heart failure. In patients with hepatic cirrhosis, the
volume of distribution is approximately doubled.
Protein binding: >99%.
Metabolism
Hepatic metabolism accounts for approximately 80% of total clearance.
Carboxylic acid derivative, the major metabolite, is inactive.

21
Route of elimination

Torsemide is cleared from the circulation by both hepatic metabolism

(approximately 80% of total clearance) and excretion into the urine
(approximately 20% of total clearance in patients with normal renal function).

Half Life

Approximately 3.5 hours.

Indications

• Treatment of hypertension alone or in combination with other antihypertensive

agents.

• Treatment of edema associated with congestive heart failure, renal disease, or

hepatic disease. Dosage and administration:

Hypertension

The usual oral initial dose is 5 mg once daily. If the 5 mg dose does not provide
adequate reduction in blood pressure within 4 to 6 weeks, the dose may be
increased to 10 mg once daily. If the response to 10 mg is insufficient, an
additional antihypertensive agent should be added to the treatment regimen.

Hepatic Cirrhosis

The usual initial dose is 5 mg or 10 mg of once-daily oral or IV torsemide,

administered together with an aldosterone antagonist or a potassium-sparing
diuretic. If the diuretic response is inadequate, the dose should be titrated upward
by approximately doubling until the desired diuretic response is obtained. Single
doses higher than 40 mg have not been adequately studied.

Congestive Heart Failure The usual initial dose is 10 mg or 20 mg of once - daily

oral or intravenous. If the diuretic response is inadequate, the dose should be

22
titrated upward by approximately doubling until the desired diuretic response is
obtained. Single doses higher than 200 mg have not been adequately studied.

Overdosage

• Symptoms include electrolyte depletion, volume depletion, hypotension,

dehydration, and circulatory collapse.

Electrolyte depletion may manifest as weakness, dizziness, mental confusion,

anorexia, lethargy, vomiting, and cramps.

Side effects of Torsemide:

The common side effects of torsemide are constipation; dizziness or light

headedness when sitting up or standing; excessive urination; headache; increased
cough; nasal inflammation; nausea. Seeking medical attention right away should
be done if any of these SEVERE side effects occur: Severe allergic reactions
(rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the
mouth, face, lips, or tongue); chest pain; diarrhea; dry mouth or unusual thirst;
hearing loss or ringing in the ears; loss of appetite; muscle pain or cramps; rapid
or irregular heartbeat; rectal bleeding; restlessness; unusual tiredness or
weakness; vomiting.

Drug Interactions

• Coadministration of torsemide was associated with significant reduction in the

renal clearance of spironolactone, with corresponding increases in the AUC.
However, clinical experience indicates that dosage adjustment of either agent is
not required.

• Because torsemide and salicylates compete for secretion by renal tubules,

patients receiving high doses of salicylates may experience salicylate toxicity
when torsemide is concomitantly administered. • The natriuretic effect of
torsemide (like that of many other diuretics) is partially inhibited by the

23
concomitant administration of indomethacin. This effect has been demonstrated
for torsemide under conditions of dietary sodium restriction (50 mEq/day) but not
in the presence of normal sodium intake (150 mEq/day).

• Coadministration of probenecid reduces secretion of torsemide into the

proximal tubule and thereby decreases the diuretic activity of torsemide. • Other
diuretics are known to reduce the renal clearance of lithium, inducing a high risk
of lithium toxicity, so coadministration of lithium and diuretics should be
undertaken with great caution, if at all. Coadministration of lithium and torsemide
has not been studied.

• Other diuretics have been reported to increase the ototoxic potential of

aminoglycoside antibiotics and of ethacrynic acid, especially in the presence of
impaired renal function. These potential interactions with torsemide have not
been studied.

Contraindications

• Allergy to torsemide

• Electrolyte depletion

• Anuria

• Renal failure

24
 AIM AND OBJECTIVES

• To formulate a pharmaceutical product that delivers the immediate-release

of torsemide for a suitable dosage form.
• Ensuring the bioavailability of torsemide by formulating a tablet that
rapidly dissolves and releases the drug in the gastrointestinal tract.
• Determining the appropriate dosage strength of torsemide to achieve the
desired therapeutic effect while minimizing the risk of adverse effects.
• Enhancing the stability of the tablet formulation to maintain the drug's
integrity during storage and handling.
• Optimizing the tablet's formulation to promote patient compliance through
ease of administration and swallowing.
• Conducting dissolution studies and pharmacokinetic evaluations to assess
the release profile and bioavailability of torsemide from the immediate-
release tablet.
• Ensuring the tablet's quality, safety, and efficacy through rigorous quality
control and adherence to regulatory guidelines.
• Establishing a cost-effective manufacturing process for the immediate-
release torsemide tablets.
• Conducting stability studies to evaluate the shelf life and storage conditions
of the formulated tablets.
• Conducting in vitro and in vivo studies to evaluate the product's
performance, efficacy, and safety profile.

25
 PLAN OF WORK

1. Selection and procurement of drug

2. Collection of excipients to be used for the formulation of tablets

3. Spectrophotometric determination of the drug selected

4. Compatibility study

5. Formulation of Immediate release tablets

6. Evaluation of Immediate release tablets:

• Hardness
• Disintegration time
• Weight variation
• Friability
• Wetting time
• In-vitro drug release
• In-vitro dissolution

26
 EXPERIMENTAL WORK

Spectroscopic Analysis and Analytical Method Development

Selection of dissolution medium for Torsemide

The selection of a dissolution medium for torsemide depends on several factors,

including the physicochemical properties of the drug, the dosage form, and the
intended use. In the case of torsemide immediate-release tablets, the dissolution
medium should mimic the physiological conditions of the gastrointestinal tract to
ensure accurate assessment of drug release.

Typically, a dissolution medium for torsemide tablets consists of a buffer solution

with a pH of 1.2 or 4.5 to simulate the acidic conditions of the stomach. These
pH values represent the pH range encountered in the gastric environment. The
buffer solution helps maintain the desired pH and provides a stable environment
for drug dissolution.

For in vitro dissolution testing, the United States Pharmacopeia (USP) and other
regulatory guidelines recommend using compendial dissolution media, such as
simulated gastric fluid (SGF) with a pH of 1.2 or acidified water, to assess the
release of tramadol hydrochloride. These media simulate the conditions in the
stomach and ensure reproducibility and comparability of dissolution results.

Development of spectrophotometric method for the estimation of Torsemide

Prparation of 0.1N HCL

Take of 8.5m.l of conc.HCL and diluted with 1000 ml of distilled water will give
a solution of pH 0.1 N HCL.

27
Standard of stock solution of 1000ppm

100 mg of torsemide was taken in a 100 ml volumetric flask ,30 ml of methanol

was added and sonicated for 15 mins. Then 0.1N HCL was added to mark upto
volume. (100ml)

Standard of stock solution of 100ppm

10ml of prepared 1000ppm solution was taken in a 100ml volumetric flask and
volume is made by 0.1N HCL.

Preparation of Aliquots

0.5,1,1.5,2,2.5,3,3.5,4 ml of 100ppm solution was taken in a10 ml volumetric

flask and volume was made up to the mark with 0.1N HCL to prepare
5,10,15,20,25,30,35,40ppm solution respectively.

Determination of λmax:

The UV spectrophotometer was set auto zero and the standard solution was
scanned to obtained the maximum wavelength absorption against blank between
wavelength 200-400nm. The standard solution was scanned for absorbance
maxima against blank. The maximum absorbance was found to be 294nm which
was fixed wavelength for Drug analysis.

Procedure for calibration curve:

The aliquots of Torsemide solution were prepared & the absorbance was
measured as max of 294 nm against reagent blank. Similarly the calibration curve
in different media was done in same manner.

28
Preparation of mouth dissolving tablet:

Solid dispersion of torsemide was taken in a motor and Micro crystalline cellulose
was added to it & triturates it, then cross providone, + starch glycolate was added
and further triturate Then all other ingredients were mixed well till powder mix
of uniform particle see obtained the tablets were prepared by direct compression
method.

Composition of oral dispersible tablet of Torsemide (all quantity in mg)

Table 1

INGREDIENT F1 F2

Torsemide 10 10

Crospovidone - 15

Sodium starch glycolate 15 -

Talc 3 3

Mg stearate 2 2

Micro crystalline 75 75
cellulose

Mannitol 45 45

TOTAL (in mg) 150 150

29
Manufacturing Process

Step 1: Sifting of the drug and the excipients, composition of tablets is mentioned
in Table. All materials were passed through sieve no. 40.

Step 2: Disintegrant was divided into two equal parts by weight. Drug
complex, one part of Superdisintegrant .

Step 3: Mixing, The sifted step 1 materials were blended for 10mins.

Step 4: Sifting, Blended mass were sifted through 40 mesh screen. Ten percent
of the fines were added to the mass and then blended for 2 minutes.

Step 5: Blending and Lubrication, remaining superdisintegrant were added to the

mass and blended for five minutes.

Step 6: Compression, the granules of the drug were compressed in a rotary

compression machine using flat faced punches of 8mm diameter.

EVALUATION PARAMETERS TO BE STUDIED FOR FAST

DISSOLVING TABLETS.

The general appearance of a tablet, its visual identity and over all
"elegance" is essential for consumer acceptance. The various evaluation testing
includes tablet's size, shape, colour, presence or absence of an odour, taste,
surface texture, physical flaws and consistency and legibility of any identifying
marking.

• Size and Shape

The size and shape of the tablet can be dimensionally described, monitored
and controlled.

30
• Weight variation:

I.P. procedure for uniformity of weight was followed, twenty tablets were
taken and their weight was determined individually and collectively on a digital
weighing balance. The average weight of one tablet was determined from the
collective weight. The weight variation test would be a satisfactory method of
determining the drug content uniformity.

• Crushing Strength

It is the force required to break a tablet by compression in the radial

direction, it is an important parameter in formulation of mouth dissolve tablets
because excessive crushing strength significantly reduces the disintegration time.
In the present study the crushing strength of the tablet was measured using Pfizer
hardness testers. An average of three observations is reported.

• Friability test (F)

The crushing test may not be the best measure of potential behavior during
handling and pack-aging. The resistance to surface abrasion may be a more
relevant parameter. Friability of each batch was measure in “Electro lab
friabilator”. Ten pre weighed tablets were rotated at 25 rpm for 4 min, the tablets
were then re weighed and the percentage of weight loss was calculated. The
friability (F) is given by the formula.

F = (W initial – W final) / W initial × 100

• Wetting time:

Five circular tissue papers of 10 cm diameter are placed in a petridish with

a 10 cm diameter. Ten millimeters of water-containing Eosin, a water-soluble
dye, is added to petridish. A tablet is carefully placed on the surface of the tissue

31
paper. The time required for water to reach upper surface of the tablet is noted as
a wetting time.

• formulation were randomly selected and in vitro dispersion time was

performed.

• In Vitro disintegration time

In Vitro disintegration time was performed by apparatus specified in USP at 50

rpm. Phosphate buffer 3.2, 900 ml was used as disintegration medium, and the
temperature of which maintained at 37±2oC and the time in second taken for
complete disintegration of the tablet with no palpable mass remaining in the
apparatus was measured in seconds.

• In vitro dissolution test

The release rate of torsemide from fast dissolving tablets is determined using
USP dissolution test apparatus II (paddle type). The dissolution test is
performed using 900ml of 0.IN HCI at 37±0.5°c and rotation speed of 50 rpm.
A sample of 5ml solution is withdrawn from the dissolution apparatus every 5
minutes for 30 minutes. after that 10 minutes time interval for next 30 minutes
and the samples are replaced with fresh dissolution medium. Absorbances of
these solutions are measured at 288 nm using UV spectrophotometer.
Cumulative percentage drug release is calculated using an equation obtained
from a standard curve.

32
 RESULTS AND DISCUSSION
The selected drug for the present work was characterized for various parameters.
Spectroscopic analysis and analytical method development was performed
thoroughly. The corresponding wavelength (λmax) for the drug to estimate in
dosage forms and its content uniformity was determined and data displayed in
following tables.

For estimation of drug in different batches of tablets calibration curve for

Torsemide was prepared in different standard solvents and linearity was observed
as per the following tables and graphs.

Table 2

Evaluation test

Evaluation test F1 F2

Hardness(kg/cm2) 3 2.7

Disintegration 1min 21sec 1min 13sec.

Friability (%) 0.47 0.44

Wetting test 2.23sec. 2.30sec

Weight variation 150+ 0.32 150+ 0.29

33
Table 3
In vitro Dissolution Test
Time(min) SSG CPV

0 0 0

5 53.12 48.35

10 62.81 56.42

15 67.39 62.53

20 71.82 66.21

25 77.91 69.63

30 82.13 71.39

40 85.37 75.41

50 88.43 80.17

60 91.57 83.91

34
Fig ; 1 In vitro dissolution absorbance curve

drug release

Table 4

concentration absorbance

0 0

5 0.189

10 0.394

15 0.579

20 0.774

25 0.985

30 1.176

35 1.384

40 1.587

35
Fig; 2

36
Fig ; 3

Calibration Curve of torsemide

Linear Plot
1.8
1.6
y = 0.0397x - 0.0082
Absorbanc

1.4
R² = 0.9998
1.2
1
0.8
e

0.6
0.4
0.2
0
-0.2 0 5 10 15 20 25 30 35 40 45

Concentration

37
 Conclusion
An effort has been made to develop a fast dissolving tablet containing torsemide
to increase its dissolution, enhancing the onset of action, therapeutic response,
patient acceptance, and ease of access. Torsemide fast dissolving tablets (FDTs)
were prepared by direct compression method using different super-disintegrants
sodium starch glycolate and crospovidone. The prepared tablets were subjected
to Hardness, weight variation, friability, disintegration time, wetting time, and in-
vitro dissolution studies. Tablet hardness and friability found to be with in the
pharmacopoeial limits which indicated that the prepared formulations were
having good mechanical strength as. The formulations which were prepared by
using of super-disintegrant Crospovidone gave the good results for tablet
disintegration, wetting time and in-vitro dissolution. However further
pharmacological studies are required to support its effectiveness.

38
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