INTRODUCTION

1. INTRODUCTION
1.1 GASTRORETENTIVE DRUG DELIVERY SYSTEM
Over the past 30 yrs, as the expense and complication involved in marketing
new drug entities have increased, with concomitant recognition of the therapeutic
advantages of controlled drug delivery, greater attention has focused on development
of sustained or controlled release drug delivery system. Several reasons for
attractiveness of the dosage form. It is recognized that for many diseased state, a
substantial number of the therapeutic compound already exist. The effectiveness of
this drug is limited by side effect of necessity to administer the compound in a clinical
setting1.
The goal in designing sustained and controlled release is to reduce frequency
of dosing or increase effectiveness of the drug by localization at site of action,
reducing dose frequency, providing uniform drug delivery 1. The current controlled
release technology had made it possible to release drugs at a constant release rate for
longer periods of time ranging from days to years. However, this benefit had not
satisfied a variety of important drugs that (i) are locally active in the stomach, (ii)
have an absorption window in the stomach or in the upper small intestine, (iii) are
unstable in the intestinal or colonic environment, or (iv) exhibit low solubilities at
high pH values. These limits promoted the development of gastroretentive
drug delivery systems (GRDDS). Besides being able to continually and sustainably
deliver drugs to the small intestinal absorption window, the improvements provided
from GRDDS include: achieving a greater and prolonged therapeutic effect and thus
reducing the frequency of administration periods, providing a more effective
treatment of local stomach disorders, and minimizing both lower-tract inactivation of
the drug and drug effects on the lower intestinal flora. However, the development
process is precluded by several physiological difficulties, such as an inability to
restrain and localize the drug delivery system (DDS) within desired regions of the
gastrointestinal (GIT) and the highly variable nature of gastric emptying process. It
can be anticipated that, depending upon the physiological state of the subject and the
design of pharmaceutical formulation, the emptying process can last from a few
minutes to 12 h.
This variability, in turn, may lead to unpredictable bio availability and times
to achieve peak plasma levels, since the majority of drugs are preferentially

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 INTRODUCTION

absorbed in the upper part of the small intestine. Furthermore, the relatively brief GET
(Gastric Emptying Time) in humans, which normally averages 2–3 h through the
major absorption zone (stomach or upper part of the intestine), can result in
incomplete drug release from the DDS leading to diminished efficacy of the
administered dose. Thus, control of placement of a DDS in a specific region of the
GIT offers numerous advantages, especially for drugs exhibiting an absorption
window in the GIT or drugs with a stability problem. Overall, the intimate contact of
the DDS with the absorbing membrane has the potential to maximize drug absorption
and may also influence the rate of drug absorption3.
From the recent scientific and patent literatures that an increased interest in novel oral
controlled release dosage forms that designed to be retained in the GIT for a
prolonged and predictable period of time exists today Several approaches are
currently utilized in the prolongation of the gastric residence times (GRT), including
floating drug delivery systems (FDDS), low-density systems, raft systems
incorporating alginate gels, bioadhesive or mucoadhesive systems, high-density
systems, super porous hydrogels and magnetic systems. The FDDS is one of the most
leading methodologies in gastroretentive drug formulations4.
Floating drug delivery systems (FDDS) or hydrodynamically controlled
systems are low-density systems that have sufficient buoyancy to float over the gastric
contents and remain buoyant in the stomach without affecting the gastric emptying
rate for a prolonged period of time. While the system is floating on the gastric
contents, the drug is released slowly at the desired rate from the system. After release
of drug, the residual system is emptied from the stomach. This results in an increased
GRT and a better control of the fluctuations in plasma drug concentration. However,
besides a minimal gastric content needed to allow the proper achievement of the
buoyancy retention principle, a minimal level of floating force (F) is also required to
keep the dosage form reliably buoyant on the surface of the meal. Many buoyant
systems have been developed based on granules, powders, capsules, tablets, laminated
films and hollow microspheres4.
1.2 ADVANTAGES OF FLOATING DRUG DELIVERY SYSTEM5
1) The principle of HBS can be used for any particular medicament or class of
medicament.

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2) The HBS formulations are not restricted to medicaments, which are principally
absorbed from the stomach. Since it has been found that these are equally efficacious
with medicaments which are absorbed from the intestine.
3) The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous
salts and for drugs meant for local action in the stomach and treatment of peptic ulcer
disease.
4) The efficacy of the medicaments administered utilizing the sustained release
principle of HBS has been found to be independent of the site of absorption of the
particular medicaments.
5) When there is vigorous intestinal movement and a short transit time as might
occur in certain type of diarrhoea, poor absorption is expected under such
circumstances it may be advantageous to keep the drug in floating condition in
stomach to get a relatively better response.
6) Gastric retention will provide advantages such as the delivery of drugs with
narrow absorption windows in the small intestinal region.
7) Many drugs categorized as once-a-day delivery have been demonstrated to have
suboptimal absorption due to dependence on the transit time of the dosage form,
making traditional extended release development challenging. Therefore, a system
designed for longer gastric retention will extend the time within which drug
absorption can occur in the small intestine.
1.3 DISADVANTAGES OF FLOATING DRUG DELIVERY SYSTEM6
1) They are not suitable candidates for drugs with stability or solubility problems in
stomach.
2) FDDS requires sufficiently high level of fluid in the stomach so that the system
can float and thus sufficient amount of water (200-250 ml) of water to be taken
together with FDDS.
3) Drugs having irritants effect on gastric mucosa are not suitable candidates for
FDDS.
4) Drugs which are absorbed along the entire GIT and which undergo first pass
metabolism may not be desired e.g. Nifedipine.

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 INTRODUCTION

1.4 BASIC GIT PHYSIOLOGY: GASTRIC EMPTYING

The stomach is anatomically divided into three parts as shown in (fig-1.1)
Fundus
Body
Antrum (pylorus)

Fig 1.1: Anatomy of stomach

The proximal stomach, made up of fundus and the body regions, serves as a reservoir
for ingested materials while the distal regions (antrum) is the major site of mixing
motions, acting as a pump to accomplish gastric emptying. Gastric emptying occurs
during fasting as well as fed states. The pattern of motility is distinct in two steps.
During the fasting state, an inter-digestive series of electric events takes place, which
cycle both through the stomach and intestine every 2-3 h. This is called as inter-
digestive myloelectric cycle or migrating myloelectric cycle (mmc), which is further
divided into 4 phases. (Fig 1.2)

Fig-1.2 Motility pattern of GIT in fasted state

1. PHASE-I: (basal phase) lasts from 30-60min with rare contractions.

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 INTRODUCTION

2. PHASE-II: (pre-burst phase) lasts for 20-40min with the intermittent action
potential and contractions as the phase progresses, the intensity and the frequency also
increases gradually.
3. PHASE-III: (burst phase) lasts for 10-20min it includes intense and regular
contractions for short period. It is due to this wave that all the undigested material is
swept out of stomach to small intestine.
4. PHASE-IV: lasts for 0-5 min and occurs between phase 3 and 1 of two consecuti
7
cycles .

Transit time
Region Surface area m2 Length M Fluid Digestible solid
GI tract 200 - - -
Stomach 0.1-0.2 - 50min 8h

Small intestine 100 3.0 2-6 h 4-9 h

Large intestine 0.5-1.0 1.5 2-6 h 2 h-3 days

8
Table 1.1 Gastrointestinal dimensions
1.5 MECHANISM OF FLOATING SYSTEMS:
Various attempts have been made to retain the dosage form in the
stomach as a way of increasing the retention time. These attempts include introducing
floating dosage forms (gas-generating systems and swelling or expanding systems),
mucoadhesive systems, high-density systems, modified shape systems, gastric-
emptying delaying devices and co-administration of gastric-emptying delaying drugs.
Among these, the floating dosage forms are the most commonly used. FDDS have a
bulk density less than gastric fluids and so remain buoyant in the stomach without
affecting the gastric emptying rate for a prolonged period of time. While the system is
floating on the gastric contents, the drug is released slowly at the desired rate from the
system. After release of drug, the residual system is eliminated from the stomach. This
results in an increased GRT and a better control of the fluctuations in plasma drug
concentration. However, besides a minimal gastric content needed to allow the proper
achievement of the buoyancy retention effect, a minimal level of floating force (F) is
also required to maintain the buoyancy of the dosage form on the
surface of the meal. To measure the floating force kinetics, a novel apparatus for
determination of resultant weight has been reported in the literature. The

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 INTRODUCTION

apparatus operates by measuring continuously the force equivalent to F (as a function

of time) that is required to maintain a submerged object. The object floats better if F is
on the higher positive side. This apparatus helps in optimizing FDDS with respect to
stability and sustainability of floating forces produced in order to prevent any
unforeseeable variations in intra-gastric buoyancy.
F = Fbuoyancy – Fgravity = (Df – Ds) g v
Where, F = total vertical force, Df = fluid density,
Ds = object density, v = volume and g = acceleration due to gravity.
Based on the buoyancy mechanism, FDDS can be classified into:
(A) single unit floating dosage systems;
(B) multiple unit floating dosage systems;
9
(C) raft forming systems .
1.6 APPROACHES TO GASTRIC RETENTION:
A number of approaches have been used to increase the GRT of a dosage form in
stomach by employing a variety of concepts. These include
a) Floating Systems:
Floating Drug Delivery Systems (FDDS) have a bulk density lower than
gastric fluids and thus remain buoyant in the stomach for a prolonged period of time,
without affecting the gastric emptying rate. While the system is floating on the gastric
contents, the drug is released slowly at a desired rate from the system. After the
release of the drug, the residual system is emptied from the stomach. This results in
anincrease in the GRT and a better control of fluctuations in the plasma drug
concentrations. Floating systems can be classified into two distinct categories, non-

10
effervescent and effervescent systems .

Fig 1.4: Drug absorption in the case of (a) Conventional dosage forms (b)
GRDDS

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 INTRODUCTION

i) Effervescent systems
Effervescent floating drug delivery systems generate gas (CO2), thus reduce the
density of the system, and remain buoyant in the stomach for a prolonged period of
time and release the drug slowly at a desired rate. The main ingredients of
effervescent system include swell able polymers like chitosan, methyl cellulose and
effervescent compounds such as citric acid, sodium bicarbonate, citric acid and

11
tartaric acid .

ii) Non-effervescent systems

This type of system, after swallowing, swells unrestrained via imbibitions of
gastric fluid to an extent that it prevents their exit from the stomach. These systems
may be referred to as the „plug-type systems‟ since they have a tendency to remain
lodged near the pyloric sphincter. One of the formulation methods of such dosage
forms involves the mixing of drug with a gel, which swells in contact with gastric
fluid after oral administration and maintains a relative integrity of shape and a bulk
density of less than one within the outer gelatinous barrier. The air trapped by the
swollen polymer confers buoyancy to these dosage forms. Examples of this type of
FDDS include colloidal gel barrier, microporous compartment system, alginate beads,
and hollow Microspheres. Another type is a Fluid- filled floating chamber which
includes incorporation of a gas-filled floatation chamber into a microporous
component that houses a drug reservoir. Apertures or openings are present along the
top and bottom walls through which the gastrointestinal tract fluid enters to dissolve
the drug. The other two walls in contact with the fluid are sealed so that the
undissolved drug remains therein. The fluid present could be air, under partial vacuum
or any other suitable gas, liquid, or solid having an appropriate specific gravity and an
inert behaviour. The device is of swallowable size, remains a float within the stomach
for a prolonged time, and after the complete release the shell disintegrates, passes off

12
to the intestine, and is eliminated

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 INTRODUCTION

Fig 1.5: Classification of Gastroretentive Drug Delivery System

Fig 1.6: Gas filled floatation chamber a. Single Layer Floating Tablets:
They are formulated by intimate mixing of drug with a gel-forming hydrocolloid,
which swells in contact with gastric fluid and maintain bulk density of less than unity.
The air trapped by the swollen polymer confers buoyancy to these dosage forms.

b. Bilayer Floating Tablets:

A bilayer tablet contain two layer one immediate release layer which release initial
dose from system while the another sustained release layer absorbs gastric fluid,
forming an impermeable colloidal gel barrier on its surface, and maintain a bulk
density of less than unity and thereby it remains buoyant in the stomach.
c. Alginate Beads:
Multi unit floating dosage forms were developed from freeze-dried calcium alginate.
Spherical beads of approximately 2.5 mm diameter can be prepared by dropping

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 INTRODUCTION

a sodium alginate solution into aqueous solution of calcium chloride, causing

precipitation of calcium alginate leading to formation of porous system, which can
maintain a floating force for over 12 h. When compared with solid beads, which gave
a short residence, time of 1 h, and these floating beads gave a prolonged residence
time of more than 5.5 h.
d. Hollow Microspheres:
Hollow microspheres (microballoons), loaded with drug in their outer polymer shells
were prepared by a novel emulsion-solvent diffusion method. The ethanol:
dichloromethane solution of the drug and an enteric acrylic polymer was poured into
0
an agitated aqueous solution of PVA that was thermally controlled at 40 C. The gas
phase generated in dispersed polymer droplet by evaporation of dichloromethane
formed an internal cavity in microsphere of polymer with drug. The microballoons
floated continuously over the surface of acidic dissolution media containing surfactant
5-12
for more than 12 h in –vitro .
2. Bio Mucoadhesive systems
Bioadhesive drug delivery systems (BDDS) are used as a delivery device within the
lumen to enhance drug absorption in a site specific manner. This approach involves
the use of bioadhesive polymers, which can adhere to the epithelial surface in the
stomach. Gastric mucoadhesion does not tend to be strong enough to impart to dosage
forms the ability to resist the strong propulsion forces of the stomach wall. The
continuous production of mucous by the gastric mucosa to replace the mucous that is
lost through peristaltic contractions and the dilution of the stomach content also seem
to limit the potential of mucoadhesion as a gastroretentive force. Some of the most
promising excipients that have been used commonly in these systems include

13
carbopol, lectins, chitosan, and etc .

a. Hydration-mediated adhesion:
Certain hydrophilic polymers tend to imbibe large amount of water and become
14
sticky, thereby acquiring bioadhesive properties .
b. Bonding-mediated adhesion:
The adhesion of polymers to a mucus or epithelial cell surface involves various
bonding mechanisms, including physical-mechanical bonding and chemical bonding.
Physical-mechanical bonds can result from the insertion of the adhesive material into
the crevices or folds of the mucosa. Chemical bonds may be either covalent (primary)

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 INTRODUCTION

or ionic (secondary) in nature. Secondary chemical bonds consist of dispersive

interactions (i.e., Vander Waals interactions) and stronger specific interactions such as
hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen
14
bonds are the hydroxyl and carboxylic groups .
3. Receptor-mediated adhesion:
Certain polymers can bind to specific receptor sites on the surface of cells, thereby
enhancing the gastric retention of dosage forms. Certain plant lectins such as tomato
lectins interact specifically with the sugar groups present in mucus or on the
14
glycocalyx .
4. Swelling/ Expanding Systems:
This is a class of gastroretentive systems capable of expanding in stomach. The
expanded structure is trapped in stomach for prolonged period leading to sustained
drug release and subsequent controlled absorption in stomach and intestine. T form in
folded and compact configuration. When exposed to gastric environment capsule shell
breaks and the dosage form attains its expanded structure, which is retained in
stomach for longer time.hese systems are administered per-orally in the form of
capsule bearing the dosage Advantages of these systems include easy formulation,
simple in operation and reproducible results; however, they suffer from serious

15
drawback like clogging of pylorus end of stomach .

5. Super porous hydrogel systems

These swellable systems differ sufficiently from the conventional types to warrant
separate classification. In this approach to improve gastric retention time (GRT) super
porous hydrogels of average pore size >100 micro miter, swell to equilibrium size
within a minute due to rapid water uptake by capillary wetting through numerous
interconnected open pores. They swell to a large size (swelling ratio: 100 or more)
and are intended to have sufficient mechanical strength to withstand pressure by
gastric contraction. This is advised by co-formulation of hydrophilic particulate
material.
6. Magnetic Systems
This approach to enhance the gastric retention time (GRT) is based on the simple
principle that the dosage form contains a small internal magnet, and a magnet placed
on the abdomen over the position of the stomach. Although magnetic system seems to
work, the external magnet must be positioned with a degree of precision that might

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 INTRODUCTION

compromise patient compliance16.

Fig 1.7: Drug release from swellable

systems 7. High-density systems:
cm-3
Basically, gastric contents have a density close to water (¨1.004 g ). When the
patient is upright small high-density pellets sink to the bottom of the stomach, where
they become entrapped in the folds of the antrum and withstand the peristaltic waves
cm-3
of the stomach wall. A density close to 2.5 g seems necessary for significant
prolongation of gastric residence time and barium sulphate, zinc oxide, iron powder,
titanium dioxide are used as excipients. Although encouraging results were reported in
ruminants, effectiveness in human beings was not observed and no system has been
marketed15-16.
8. Raft systems:
Raft forming systems have received much attention for the delivery of antacids and
drug delivery for gastrointestinal infections and other disorders. The mechanism
involved in the raft formation includes the formation of a viscous cohesive gel in
contact with gastric fluids, wherein each portion of the liquid swells forming a
continuous layer called a raft. This raft floats on gastric fluid because of the low bulk
density created by the formation of CO2. Usually, the system contains a gel forming
agent and alkaline bicarbonates or carbonates responsible for the formation of CO 2 to
make the system less dense and able to float on the gastric fluids17.

1.8 CRITERIA FOR SELECTION OF DRUGS20

Certain types of drugs only benefit for gastro retentive devices. These include:
Drugs acting locally in the stomach.Exhibit site-specific absorption It must have
sufficient structure to form a cohesive gel barrier.It must maintain an overall specific
gravity less than that of gastric content.It should dissolve slowly enough to serve
as a “Reservoir” for the delivery system20

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 INTRODUCTION

.1.9 POLYMERS AND OTHER INGREDIENTS FOR FLOATING

DRUG
DELIVERY SYSTEM21
Following types of ingredients can be incorporated into HBS
(hydrodynamically balanced system) dosage form in addition to the drugs: HPMC K4
M, Calcium alginate, Eudragit S100, Eudragit RL, Propylene foam, Eudragit RS,
ethyl cellulose, poly methyl methacrylate, Methocel K4M, Polyethylene oxide, β
Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate,
PVA, Polycarbonate, Sodium alginate, Eudragit S, HPMC, Metolose S.M. 100,
PVP,HPMC K15, Polyox, HPMC K4, Acrylic polymer, E4 M andCarbopol21.

a. Inert fatty materials (5%-75%):

Edible, inert fatty materials having a specific gravity of less than one can be used to
decrease the hydrophilic property of formulation and hence increase buoyancy. E.g.
Beeswax, fatty acids, long chain fatty alcohols,
b. Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-
Sodium Glycine Carbonate, CG (Citroglycine).
c. Release rate accelerants (5%-60%) : e.g. lactose, mannitol
d. Release rate retardants (5%-60%): e.g. Dicalcium phosphate, talc, magnesium
stearate.
e. Buoyancy increasing agents (upto80%): e.g. Ethyl cellulose.
f. Low density material: Polypropylene foam powder (Accurel MP 1000).
1.11 FACTORS AFFECTING GASTRIC RETENTION23
Various attempts have been made to retain the dosage forms in the stomach as
a way of increasing the retention time. The various factors which influence the
efficacy of GRDF`s as a gastro-retentive systems are:
a. Density: GRT is a function of dosage form buoyancy that is dependent on the
density.
b. Size: Dosage form units with a diameter of more than 7.5 mm are reported to have
an increased GRT compared with those with a diameter of 9.9 mm.
c. Shape of dosage form : Tetrahedron and ring shaped devices with a flexural
modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better

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 INTRODUCTION

GRT = 90% to100% retention at 24 h compared with other shapes.

d. Single and multiple unit formulations: Multiple unit formulations show a more
predictable release profile and insignificant impairing of performance due to failure of
units, allow co-administration of units with different release profiles or containing
incompatible substances and permit a larger margin of safety against dosage form
failure compared with single unit dosage forms.
e. Fed or unfed state: Under fasting conditions, the GI motility is characterized by
periods of strong motor activity MMC that occurs every 1.5 to 2 h. The MMC sweeps
undigested material from the stomach and, if the timing of administration of the
formulation coincides with that of the MMC, the GRT of the unit can be expected to
be very short. However, in the fed state, MMC is delayed and GRT is considerably
longer.
f. Nature of meal: Feeding of indigestible polymers or fatty acids salts can change
the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying
rate and prolonging drug release.
g. Caloric content of meal: GRT can be increased by 4 to 10 h with a meal that is
high in proteins and fats.
h. Frequency of feed: The GRT can be increased by over 400 min when successive
meals are given compared with a single meal due to the low frequency of MMC.
i. Gender: Mean ambulatory GRT in males (3.4 ± 0.6 h) is less compared with their
age and race matched female counter parts (4.6 ± 1.2 h) regardless of the weight,
height and body surface.
j. Age: Elderly people, especially those above 70 yrs, have a significantly longer
GRT.
k. Posture: GRT can vary between supine and upright ambulatory states of the
patient.
l. Concomitant drug administration: Drugs that are gastric emptying include poorly
soluble antacids (aluminium hydroxide), anticholinergics (atropine, propantheline),
narcotic analgesics (morphine) and tricyclic anti depressants (imipramine,
amitriptyline.
m. Biological factors: Diseases like gastroenteritis, gastric ulcer, pyloric stenosis,
diabetes and hypothyroidism retard gastric emptying. Partial or total gastrectomy,
duodenal ulcer and hypothyroidism promote gastric emptying rate.

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 INTRODUCTION

24
1.12 APPLICATION OF FLOATING DRUG DELIEVERY SYSTEM :
a. Enhanced bioavailability:
The bioavailability of riboflavin CRGRDF is significantly enhanced in comparison to
the administration of non CRGRDF polymeric formulations. There are several
different processes, related to absorption and transit of the drug in the gastrointestinal
tract, that act concomitantly to influence the magnitude of drug absorption.
b. Sustained drug delivery:
Oral CR formulations are encountered with problems such as gastric residence time in
the GIT. These problems can be overcome with the HBS systems which can remain in
the stomach for long periods and have a bulk density <1 as a result of which they can
float on the gastric contents. These systems are relatively larger in size and passing
from the pyloric opening is prohibited.
c. Site –specific drug delivery systems:
These systems are particularly advantageous for drugs that are specifically absorbed
from the stomach or the proximal part of the small intestine . The controlled, slow
delivery of drug to the stomach provides sufficient local therapeutic levels and limits
the systemic exposure to the drug. This reduces side effects that are caused by the
drug in the blood circulation. In addition, the prolonged gastric availability from a site
directed delivery system may also reduce the dosing frequency.eg: Furosemide and
Riboflavin.
d. Absorption enhancement:
Drugs which are having poor bioavailability because of site specific absorption from
the upper part of the GIT are potential candidates to be formulated as floating drug
delivery systems, there by maximizing their absorption.
e. Minimized adverse activity at the colon:
Retention of the drug in the HBS systems at the stomach minimizes the amount of
drug that reaches the colon. Thus, undesirable activities of the drug in colon may be
prevented. This pharmacodynamic aspect provides the rationale for GRDF
formulation for betalactam antibiotics that are absorbed only from the small intestine,
and whose presence in the colon leads to the development of microorganism‟s
resistance.

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 INTRODUCTION

concentrations within a narrower range compared to the immediate release dosage

forms. Thus, fluctuations in drug effects are minimized and concentration dependent
adverse effects that are associated with peak concentrations can be prevented. This
feature is of special importance for drugs with a narrow therapeutic index.

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 REVIEW OF LITERATURE
2. REVIEW OF LITERATURE
Ramesh Bomma et al ., developed Floating matrix tablets of norfloxacin by the wet
granulation technique, using polymers such as hydroxypropyl methylcellulose
(HPMC K4M, HPMC K100M) and xanthan gum. Tablets were evaluated for their
physical characteristics, viz., hardness, thickness, friability, and mass variation, drug
content and floating properties. Further, tablets were studied for in vitro drug release
characteristics for 9 hours.
Mahesh C et al26., developed gastroretentive dosage forms for ofloxacin. Design of
the delivery system was based on the sustained release formulation, with floating and
swelling features in order to prolong the gastric retention time of the drug delivery
systems. Different polymers, such as psyllium husk, HPMC K100M, crospovidone
and its combinations were tried in order to get the desired sustained release profile
over a period of 24 h.
Sangeka S et al27., studied the effect of food and specific gravity on the gastric
retention time of floating (spec. grav. 0.96) and non-floating (spec. grav. 1.59) tablet
formulations was investigated using gamma scintigraphy in humans. The results
obtained indicate that the presence of food in the stomach appears to significantly
prolonged gastric retention of both the floating and non-floating tablets while specific
gravity does not seem to play an important role in the residency time of the tablets in
the stomach.
Yalçın Özkan et al28., studied the effects of formulation variables on the release
profile of Diclofenac sodium (DS) from hydroxy propyl methyl cellulose (HPMC)
and chitosan matrix tablets were studied. DS tablets were prepared by wet granulation
and direct compression methods and different ratios of HPMC and chitosan were
used. In-vitro studies showed that 20% HPMC contained SR formulation with direct
(dry) compression method is the optimum formulation due to its better targeting
profile in terms of release. This formulation also exhibited the best-fitted formulation
into the zero order kinetics. The precision and accuracy of the analytical method were
also checked. The repeatability and reproducibility of the method were also
determined.
Bodmeier R et al29., studied and developed floating controlled drug delivery system
consisting of (i) polypropylene foam powder, (ii) matrix-forming polymer(s), (iii)
drug, and (iv) filler (optional).By using different types of matrix-forming polymers
were studied: hydroxypropyl methylcellulose (HPMC), polyacrylates, sodium
alginate, corn starch, carrageenan, gum guar and gum arabic.

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 REVIEW OF LITERATURE
The highly porous foam powder provided low density and, thus, excellent in vitro
floating behavior of the tablets. All foam powder-containing tablets remained floating
for at least 8 h in 0.1 N HCl at 37 0C.
Javed A et al30., developed a hydrodynamically balanced system of metformin as a
single unit floating capsule. Various grades of low-density polymers were used for
the formulation of this system. They were prepared by physical blending of
metformin and the polymers in varying ratios. The formulation were optimized on the
basis of in vitro buoyancy and in vitro release in simulated fed state gastric fluid
(citrate phosphate buffer pH 3.0). Effect of various release modifiers was studied to
ensure the delivery of drug from the HBS capsules over a prolonged period. Capsules
prepared with HPMC K4M and ethyl cellulose gave the best in vitro percentage
release and were taken as the optimized formulation.
Ramesh C. et al31., studied an oral sustained release dosage form of Cinnarizine HCl
(CNZ) based on gastric floating matrix tablets. The release of CNZ from different
floating matrix formulations containing four viscosity grades of hydroxypropyl
methylcellulose, sodium alginate or polyethylene oxide, and gas forming agent
(sodium bicarbonate or calcium carbonate) were studied in simulated gastric fluid
(pH 1.2). CNZ release data from the matrix tablets were analyzed kinetically using
Higuchi, Peppas, Weibull, and Vergnaud models.
Chien W Y et al32., studied and investigated the effect of formulation variables on
drug release and floating properties of the delivery system. Hydroxypropyl
methylcellulose (HPMC) of different viscosity grades and Carbopol 934P (CP934)
were used in formulating the Gastric Floating Drug Delivery System (GFDDS)
employing 2 × 3 full factorial design. Main effects and interaction terms of the
formulation variables could be evaluated quantitatively by a mathematical model. It
was found that both HPMC viscosity, the presence of Carbopol and their interaction
had significant impact on the release and floating properties of the delivery system.
The decrease in the release rate was observed with an increase in the viscosity of the
polymeric system. Polymer with lower viscosity (HPMC K100LV) was shown to be
beneficial than higher viscosity polymer (K4M) in improving the floating properties
of GFDDS. Incorporation of Carbopol, however, was found to compromise the
floating capacity of GFDDS and release rate of calcium

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 REVIEW OF LITERATURE
Paloma F et al33., studied and formulated matrix system of an active principle,
metoclopramide hydrochloride, scattered into a biocompatible hydrophobic
polymerical mesh, polyamide 12, to achieve sustained and controlled delivery of
metoclopramide hydrochloride. This research was conducted to investigate the in
vitro drug release behavior from these new inert polymeric matrix tablets. The drug
release process was investigated both experimentally and by means of mathematical
models. Different models were applied for the evaluation of drug release data.
Additionally, the influence of the experimental conditions of the dissolution devices,
such as rate of flow and pH of dissolution medium, on the parameters that
characterize the release mechanism was studied, and it was found that the main factor
was the hydrodynamic condition of rate of flow.
Leopoldo V R et al34., developed a controlled release formulation of captopril. In this
work, the in vitro sustained release of captopril from Metolose SH 4000 SR/sodium
bicarbonate floating tablets has been studied, varying the proportions of Metolose and
bicarbonate. This was studied at two different compaction pressures. Other variables
include the kinetics of the hydration volume, the matrices floating time and the matrix
density. The results show that matrices compacted at 55MPa float in the dissolution
medium for more than 8 h while those compacted at 165MPa float only when sodium
bicarbonate is included in the formulation. The drug released with time is lesser when
sodium bicarbonate is included in the formulation.
Julijana K et al35., developed floating matrix tablets, which after oral administration
are designed to prolong the gastric residence time, increase the drug bioavailability
and diminish the side effects of irritating drugs. Tablets containing hydroxypropyl
methylcellulose (HPMC), drug and different additives were compressed. The
investigation shows that tablet composition and mechanical strength have the greatest
influence on the floating properties and drug release. With the incorporation of a gas-
generating agent together with microcrystalline cellulose, besides optimum floating
(floating lag time, 30 s; duration of floating, >8 h),

Page 18
 REVIEW OF LITERATURE
Gangadharappa HV, et al36., formulated and evaluated Atenolol floating tablets
based on gas formation technique was developed in order to prolong the gastric
residence time and to increase the overall bioavailability of the dosage form.The
floating dosage forms which exhibit prolonged residence in the stomach. They
showed a satisfactory dissolution profile, floating lag time and floating
characteristics. The tablets remained floating for up to 24 h.
Patel JK, et al37., studied the effects of formulation and processing parameters on a
floating matrix controlled drug delivery system consisting of a poly (styrene-divinyl
benzene) copolymer low density powder, a matrix-forming polymer(s), drug, and
diluents (optional). The tablets were prepared by the direct compression technique
which shows that the Hydroxypropyl Methyl Cellulose (HPMC K100M), which is
often used in hydrophilic matrix drug delivery systems, can be used to modify the
release rates in hydrophilic matrix tablets prepared by direct compression. A 15%
(w/w) low density copolymer (based on the mass of the tablet) was sufficient to
achieve proper in vitro floating behavior for at least 8 h.
Puneeth KP, et al38., studied the floating tablets of Rosiglitazone maleate which was
developed using gas forming agents, like sodium bicarbonate, tartaric acid and
polymers like Hydroxypropyl Methyl Cellulose (HPMC K15M) and xanthan gum.
The prepared tablets evaluated in terms of their precompression parameters, physical
characteristics, in- vitro release, buoyancy and buoyancy lag time. The in vitro drug
release profiles obtained for formulation containing xanthan gum showed controlled
drug release for 12h.
Viral FP, et al39., studied the development of controlled release dosage form for
poorly soluble drug, polymer blends of different viscosity grade of Hydroxypropyl
Methyl Cellulose (HPMC) and presence of surfactant appears necessary, which
imparts hydrophilic environment and wettability to molecules of drug leads to more
uniform drug release, respectively.
Rishad RJ, et al40., described the design and development of self-correcting
monolithic gastroretentive system of Baclofen. Tablets were prepared by direct
compression method. It was observed that for the development of controlled-release
dosage form of Baclofen, polymer like Polyethylene Oxide (PEO) which imparts
hydrophilic environment leads to more uniform drug release.

Page 19
 REVIEW OF LITERATURE

Satish SK, et al41., studied the floating drug delivery with controlled release of
Celecoxib using Hydroxypropyl Methyl Cellulose (HPMC) and Ethyl Cellulose (EC)
as a carrier. In vitro dissolution studies should controlled release for 24 h.
Ravi K, et al42., described the preparation of floating tablets of Famotidine. The
effervescent-based floating drug delivery was a promising approach to achieve in
vitro buoyancy. The addition of gel-forming polymer Hydroxypropyl Methyl
Cellulose (HPMC K4 M, HPMC K15 M), carbopol 934P and gas-generating agent
sodium bicarbonate was essential to achieve in vitro buoyancy. Since the formulation
showed sufficient release for prolonged period, the dose can be reduced and possible
incomplete absorption of the drug can be avoided.
Mina IT, et al43., developed controlled-release floating tablets of Cipro HCl were
successfully formulated by effervescent technique. Tablets containing Hydroxypropyl
Methylcellulose (HPMC K15M), Na alginate and NaHCO3 or CaCO3 showed
satisfactory results with respect to floating lag time, total floating duration, swelling
ability, adhesion retention period and sustained drug release rates.
Omray L. K. et al44., developed floating drug delivery system (FDDS) of acyclovir
containing polyvinyl pyrrolidon (PVP), polyvinyl alcohol (PVA) and hydroxy propyl
methyl cellulose (HPMC) as the polymers and sodium bicarbonate as a gas
generating agent, to reduce floating lag time. The FDDS tablets were prepared by wet
granulation method. Five formulations were developed which differed in the ratio of
polymers. All the formulations were evaluated for hardness, friability, weight
variation, drug content uniformity, buoyancy studies, swelling index and in vitro drug
release study.
Punitha.K* et al45., prepred floating microspheres of Ranitidine Hydrochloride withn
HPMC 15 cps and Eudragit E‐100 in various ratios of 1:1, 1:2, and 1:3. Floating
microspheres were aimed to achieve an extended retention in the upper gastrointestinal
tract, which may result in enhanced absorption and thereby improved bioavailability.
The formulations were evaluated for FTIR, drug loading, % entrapment, particle size,
SEM, buoyancy, dissolution study and the drug release kinetics. The enhanced
floatability of the formulation and its retention in GIT may attribute for the increased
bioavailability and decrease in frequency of administration. Comparison of both the
polymers revealed HPMC to be a suitable candidate for sustained release.

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 REVIEW OF LITERATURE
Shankraiah M et al46., developed new intra-gastric floating microspheres for
controlled delivery of levofloxacin for the treatment of peptic ulcer caused by
Helicobacter pylori (H. pylori). Floating microspheres of levofloxacin were prepared
by emulsion solvent evaporation technique. The drug was encapsulated with HPMC
and Eudragit S 100 in different polymers ratios. The % Yield of microspheres was
high in HPMC batches over Eudragit S 100 batches. The particle sizes of
microspheres were increased by increasing the polymer concentration. Percentage
Buoyancy of microspheres were found to be in the range of 63.38%, 75.58%
indicated that most of the microspheres were still floatable after 12hours because of
their low density and internal voids. Microspheres of levofloxacin with HPMC
showed enhanced release rate when compared to levofloxacin with Eudragit S 100.
Ming-Thau S et al47., study was to develop an optimal gastroretentive drug delivery
system (GRDDS) for administering Losartan. Additionally, the influence of
optimized GRDDS on the bioavailability of Losartan and the formation extent of
active metabolite E3174 by CYP2C9 polymorphism was investigated. Swellable and
floatable GRDDS tablets combining hydroxyethyl cellulose (HEC), sodium
carboxymethyl cellulose (NaCMC), and sodium bicarbonate were prepared at various
compression pressures for evaluating swelling characteristics and floating capacity.
Then Losartan was incorporated into optimized formulations for in vitro and in vivo
characterizations.
Baljit S et al48., studied that to improve the bioavailability and therapeutic efficacy of
the drugs used for the diseases associated with the stomach, the retention of drug
delivery systems in the stomach for longer time is requred. an attempt has been made
to synthesize gastro-retentive floating drug delivery system by simultaneously
ionotropic gelation of alginate and sterculia gum by using CaCl2 as crosslinker. The
beads thus formed have been characterized by scanning electron micrographs
(SEMs), electron dispersion X-ray analysis (EDAX), Fourier transform infrared
spectroscopy (FTIR) analysis. The swelling of beads has been carried out as a
function of various reaction parameters and pH of the swelling media. In addition, in
vitro release dynamics of anti-ulcer model drug pantoprazole from drug loaded beads
in different release media has been carried out for the evaluation of the drug release
mechanism and diffusion coefficients.

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 REVIEW OF LITERATURE
PatilS.B. et al49., studied that Zolpidem tartarate is a non-benzodiazepine, sedative-
hypnotic, which finds its major use in various types of insomnia. The work relates to
development of multiparticulate floating drug delivery system based on gas
generation technique to prolong the gastric residence time and to increase the overall
bioavailability. Modified release dosage form of zolpidem tartarate adapted to release
over a predetermined time period, according to biphasic profile of dissolution, where
the first phase is immediate release phase for inducing the sleep and the second phase
is modified release phase for maintaining the sleep up to 10 h. The system consists of
zolpidem tartarate layered pellets coated with effervescent layer and polymeric
membrane. The floating ability and in vitro drug release of the system were
dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the
drug layered pellets, and coating level of the polymeric membrane (Eudragit® NE
30D). The system could float completely within 5 min and maintain the floating over
a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate
with rapid floating and modified drug release was obtained.

Jaber E et al50., developed a prolonged release gastroretentive (GT) formulation of

ciprofloxacin that could be administered once daily with a conventional tablet (CT).
A variety of polymers and effervescent properties were utilized to optimize the
desired disposition profile. Tablets were prepared by the direct compression
technique and evaluated for physical properties, swelling, floating, and drug release.
In vivo studies were also carried out on the optimized GT formulation and CT in
healthy volunteers. A very sensitive and reliable HPLC method was developed to
measure plasma concentration of ciprofloxacin. The duration of floating times were
predominantly >24 h and floating lag times <20 s. w/w), Na alginate (7.14%, w/w)
and NaHCO3 (20%, w/w) (formula F7) or CaCO3 (20%, w/w) (formula F10) were
promising systems exhibiting excellent floating properties, extended adhesion periods
and sustained drug release characteristics.

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 Drug and Excipient profile

3. DRUG PROFILE:
Famotidine

Famotidine (INN) is a second generation histamine H2 receptor antagonist having

multimodal mechanism of action and used to treat gastrointestinal disorders.
Structure:

Formula Molecular
: C8H15N7O2S3
mass
: 337.435 g/mol
(IUPAC) name

3-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]-~{N}'-
sulfamoylpropanimidamide
Pharmacodynamics
Famotidine interferes with the histamine interaction and binding with parietal cells of the
duodenum that involved in gastric acid secretion. Inhibition of histamine binding reduces
overall acid production in duodenal cells. Famotidine selectively binds with the histamine
(H2) receptors.
Pharmacokinetics
After oral administration, Famotidine is rapidly absorbed in the GIT. The plasma protein
binding capability of Famotidine is 88%. The drug is predominantly metabolized via
CYP2D6 and CYP3A4 enzymes. Famotidine is mostly excreted in urine as drug
metabolites and as unchanged drug, to some extent.
Precautions
Famotidine is contraindicated in patients with renal and hepatic impairment.
Other Drug Interactions
Famotidine may interact with diuretics, lornoxicam, ACE inhibitors, lithium,
anticoagulants, methotrexate and cimetidine.
 Drug and Excipient profile
Medical use
Famotidine is used to treat gastric ulcers, duodenal ulcers, stomal ulcers, wounds in the
lining of the stomach associated with acute gastritis and with acute exacerbation of
chronic gastritis.
Mechanisms of action
Like other H2 receptor antagonists it prevents the secretion of gastric acid.[2] It also
activates calcitonin gene related peptide, resulting in the stimulation of nitric oxide (NO)
and regulation of gastric mucosal blood flow, increases somatostatin levels also resulting
in less gastric acid secretion, causes the stomach lining to generate more mucin, inhibits
neutrophil activation thus preventing injury from inflammation, and blocks the
attachment of H. pylori to gastric cells.
Melting point : 96 ~ 99 C
half-life : 1.92 ± 0.94 h
Adverse effects
Adverse events observed during clinical trials included constipation, diarrhea, drug rash,
nausea or vomiting and dizziness
Storage Conditions : Store it at room temperature.
3.2 POLYMER PROFILES
HYDROXY PROPYL METHYL CELLULOSE

Fig: 3.2 Structural formula of HPMC

Page 24
 Drug and Excipient profile
Non proprietary Names
BP: Hypromellose JP:
Hypromellose PhEur:
Hypromellose USP:
Hypromellose
Synonyms
Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; hypromellosum;
Methocel; methylcellulose propylene glycol ether; methyl hydroxypropylcellulose;
Metolose; MHPC; Pharmacoat; Tylopur; Tylose MO.HPMCK100.
Chemical Name and CAS Registry Number
Cellulose hydroxypropyl methyl ether
Functional Category
Bioadhesive material; coating agent; controlled-release agent; dispersing agent;
dissolution enhancer; emulsifying agent; emulsion stabilizer; extended-release agent;
film-forming agent; foaming agent; granulation aid; modified-release agent.
mucoadhesive; release-modifying agent; solubilizing agent; stabilizing agent;
suspending agent; sustained-release agent; tablet binder; thickening agent; viscosity-
increasing agent.
Description: Hypromellose is an odorless and tasteless, white or creamy-white
fibrous or granular powde
Typical properties
Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous solution.
Density (bulk): 0.341 g/cm3.
Density (tapped): 0.557 g/cm3.
Density (true): 1.326 g/cm3.
Melting point: Melting point of HPMC is 170–180°C.
Solubility:
Soluble in cold water, forming a viscous colloidal solution; practically insoluble in
chloroform, ethanol (95%) and ether, but soluble in mixtures of ethanol and
dichloromethane, mixtures of methanol and dichloromethane, and mixtures of water and
alcohol.

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 Drug and Excipient profile
Applications in pharmaceutical formulation or technology
Hypromellose is widely used in oral, ophthalmic and topical pharmaceutical
formulations. In oral products, hypromellose is primarily used as a tablet binder, in film-
coating, and as a matrix for use in extended-release tablet formulations. Concentration
between 2% and 5% w/w may be used as a binder in either wet or dry granulation
processes. High-viscosity grades may be used to retard the release of drugs from a matrix
at levels of 10–80% w/w in tablets and capsules. Depending upon the viscosity grade;
concentration of 2–20% w/w are used for film-forming solutions to film-coat tablets.
Lower-viscosity grades are used in aqueous film-coating solutions while higher-viscosity
grades are used with organic solvents.
Viscosity (dynamic)
Table 3.2 Methocel Grades

Methocel product USP designation Nominal viscosity (mPa s)

Methocel K100 premium 2208 100
Methocel K4M premium 2208 4000
Methocel K15M premium 2208 15 000
Methocel K100M premium 2208 100 000
Methocel E4M premium 2910 4000
Methocel F50 premium 2906 50
Methocel E10M premium 2906 10 000
Methocel E3 premium LV 2906 3
Methocel E15 Premium LV 2910 15

A wide range of viscosity types are commercially available (table 3.1). Aqueous
solutions are most commonly prepared; Dichloromethane and ethanol mixtures may also
be used to prepare viscous hypromellose solutions. Solutions prepared using organic
solvents tend to be more viscous; increasing concentration also produces more viscous
solutions.
Typical viscosity values for 2% (w/v) aqueous solutions of methocel, viscosities
measured at 20°C.

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 Drug and Excipient profile

To prepare an aqueous solution, it is recommended that hypromellose is

dispersed and thoroughly hydrated in about 20–30% of the required amount of
water.The water should be vigorously stirred and heated to 80–90°C and then the
remaining hypromellose should be added. Then sufficient cold water should be added to
produce the required volume.
Incompatibilities: Hypromellose is incompatible with some oxidizing agents. Since it is
nonionic, hypromellose will not complex with metallic salts or ionic organics to form
insoluble precipitates.
XANTHAN GUM
Synonyms :Corn sugar gum; Merezan; Rhodigel. Chemical
name :Xanthan gum 6

I t i s a Stabilizing, suspending, and viscosity building agent.

It is widely used as suspending, thickening, stabilizing and emulsifying agent. It is
also used to prepare sustained-release matrix tablets.
It occurs as a cream or white colored odorless free flowing fine powder.
Solubility : Practically insoluble in ethanol and ether;soluble in cold
and warm water.
Viscosity :1200-1600 mPa s for 1% w/v aqueous solution
It incompatible with cationic surfactants, polymers, preservatives, oxidizing agents,
Sod. CMC, Verapamil.
Stability and storage conditionStable material at wide range of pH and temperature. It
should be stored in a well closed container in a cool, dry place It regarded as nontoxic
and nonirritant at the level employed as pharmaceuticalexcipient.

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 Drug and Excipient profile
CELLULOSE, MICROCRYSTALLINE

Fig: 3.4 Structure of Cellulose, Microcrystalline

Nonproprietary Names
BP: Microcrystalline Cellulose JP:
Microcrystalline Cellulose PhEur:
Cellulose, Microcrystalline USP-NF:
Microcrystalline Cellulose Synonyms
Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristallinum; Celphere;
Ceolus KG; crystalline cellulose; E460; Emcocel; Ethispheres; Fibrocel; MCC Sanaq;
Pharmacel; Tabulose; Vivapur.
Chemical Name and CAS Registry Number
Cellulose.
Functional Category
Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant.
Description
Microcrystalline cellulose is purified, partially depolymerized cellulose that occurs as a
white, odorless, tasteless, crystlline powder composed of porous particles. It is
commercially available in different particle sizes and moisture grades that have
different properties and applications.
Typical Properties
Angle of repose: 34.4º for Emcocel 90m.0.337 g/cm3,0.32 g/cm3 for Avicel PH-101
Density (tapped)
0.478 g/cm3;0.45 g/cm3 for Avicel PH-101

Page 28
 Drug and Excipient profile
Density (true)
1.512–1.668 g/cm3;
1.420–1.460 g/cm3 for Avicel PH-102.
Flowability
1.41 g/s for Emcocel 90M.
Melting point Chars at 260–2700C.
Solubility
Slightly soluble in 5% w/v sodium hydroxide solution; practically insoluble in water,
dilute acids, and most organic solvents.
Stability and Storage Conditions
Microcrystalline cellulose is a stable though hygroscopic material. The bulk material
should be stored in a well-closed container in a cool, dry place.
Incompatibilities
Microcrystalline cellulose is incompatible with strong oxidizing agents.
Applications in Pharmaceutical Formulation or Technology
Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a
binder/diluent in oral tablet and capsule formulations where it is used in both wet-
granulation and direct-compressio processes. In addition to its use as a binder/diluent,
microcrystalline cellulose also has some lubricant and disintegrant properties that make it
useful in tableting.
SODIUM BICARBONATE
Nonproprietary Names
BP: Sodium Bicarbonate
JP: Sodium Bicarbonate
PhEur: Sodium Hydrogen Carbonate
USP: Sodium Bicarbonate
Synonyms
Baking soda; E500; Effer-Soda; monosodium carbonate; natrii hydrogenocarbonas;
Sal de Vichy; sodium acid carbonate; sodium hydrogen carbonate.
Chemical Name and CAS Registry Number
Carbonic acid monosodium salt

Page 29
 Drug and Excipient profile
Description
Sodium bicarbonate occurs as an odorless, white, crystalline powder with a saline,
slightly alkaline taste. The crystal structure is monoclinic prisms. Grades with different
particle sizes, from a fine powder to free-flowing uniform granules, are commercially
available.
Typical Properties
Acidity/alkalinity
pH = 8.3 for a freshly prepared 0.1M aqueous solution at 25 0C; alkalinity increases on
standing, agitation, or heating.
Density (bulk) 0.869 g/cm3
Density (tapped) 1.369 g/cm3
Density (true) 2.173 g/cm3
Freezing point depression 0.3818C (1% w/v solution)
Melting point 2700C (with decomposition)
Table: 3.3 Solubility of sodium bicarbonate.

Solvent Stated Solubility at 200C unless otherwise

Ethanol (95%) Practically insoluble

Ether Practically insoluble

Water 1 in 11

1 in 4 at 100 0C(a)
1 in 10 at 25 0C

1 in 12 at 18 0C

Stability and Storage Conditions

Sodium bicarbonate is stable in dry air but slowly decomposes in moist air and
should therefore be stored in a well-closed container in a cool, dry place.

Page 30
 Drug and Excipient profile
Applications in Pharmaceutical Formulation or Technology
Sodium bicarbonate is generally used in pharmaceutical formulations as a source
of carbon dioxide in effervescent tablets and granules. It is also widely used to produce
or maintain an alkaline pH in a preparation. In effervescent tablets and granules, sodium
bicarbonate is usually formulated with citric and/or tartaric acid; combinations of citric
and tartaric acid are often preferred in formulations as citric acid alone produces a sticky
mixture that is difficult to granulate, while if tartaric acid is used alone, granules lose
firmness.
Sodium bicarbonate has also been used as a freeze-drying stabilizer and in
toothpastes. Recently, sodium bicarbonate has been used as a gas-forming agent in
alginate raft systems and in floating, controlled release oral dosage forms for a range of
drugs. Sodium bicarbonate has also been included in formulations of vaginal bioadhesive
tablets and in carbon dioxide releasing suppositories. Therapeutically, sodium
bicarbonate may be used as an antacid, and as a source of the bicarbonate anion in the
treatment of metabolic acidosis. Sodium bicarbonate may also be used as a component of
oral rehydration salts and as a source of bicarbonate in dialysis fluids. Sodium
bicarbonate is used in food products as an alkali or as a leavening agent, e.g. baking
soda.
MAGNESIUM STEARATE
Nonproprietary Names BP:
Magnesium Stearate JP:
Magnesium Stearate
PhEur: Magnesium Stearate
USP-NF: Magnesium Stearate
Synonyms
Dibasic magnesium stearate; magnesium distearate; magnesium stearas; magnesium
octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt.
Chemical Name
Octadecanoic acid magnesium salt
Structural Formula
[CH3(CH2)16COO]2Mg

Page 31
 Drug and Excipient profile
Description
Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder
of low bulk density, having a faint odor of stearic acid and a characteristic taste. The
powder is greasy to the touch and readily adheres to the skin.
Typical Properties
Crystalline forms High-purity magnesium stearate has been isolated as a trihydrate, a
dihydrate, and an anhydrate.
Density (bulk) 0.159 g/cm3
Density (tapped) 0.286 g/cm3
Density (true) 1.092 g/cm3
Flowability
Poorly flowing, cohesive powder.
0 0
Melting point: 117–150 C (commercial samples); 126–130 C (high purity
magnesium stearate).
Solubility
Practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in warm
benzene and warm ethanol (95%).
Stability and Storage Conditions
Magnesium stearate is stable and should be stored in a well-closed container in a cool,
dry place.
Applications in Pharmaceutical Formulation or Technology
Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical
formulations. It is primarily used as a lubricant in capsule and tablet manufacture at
concentrations between 0.25% and 5.0% w/w. It is also used in barrier creams.
TALC
Nonproprietary Names
BP: Purified Talc
JP: Talc
PhEur: Talc
USP: Talc

Page 32
 Drug and Excipient profile
Synonyms
Altalc; E553b; hydrous magnesium calcium silicate; hydrous magnesium silicate;
Imperial; Luzenac Pharma; magnesium hydrogen metasilicate; Magsil Osmanthus;
Magsil Star; powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore;
talcum.
Chemical Name and CAS Registry Number
Talc
Description
Talc is a very fine, white to grayish-white, odorless, impalpable, unctuous,
crystalline powder. It adheres readily to the skin and is soft to the touch and free
from grittiness. Typical Properties
Acidity/alkalinity
pH = 7–10 for a 20% w/v aqueous dispersion
Solubility
Practically insoluble in dilute acids and alkalis, organic solvents, and water.
Specific gravity 2.7–2.8
Applications in Pharmaceutical Formulation or Technology
Talc was once widely used in oral solid dosage formulations as a lubricant and
diluent, although today it is less commonly used. However, it is widely used as
adissolution retardant in the development of controlled-release products. Talc is also
used as a lubricant in tablet formulations; in a novel powder coating for extended-release
pellets; (8) and as an adsorbant. In topical preparations, talc is used as a dusting powder,
although it should not be used to dust surgical gloves. Talc is a natural material; it may
therefore frequently contain microorganisms and should be sterilized when used as a
dusting powder. Talc is additionally used to clarify liquids and is also used in cosmetics
and food products, mainly for its lubricant properties.
Stability and Storage Conditions:
0
Talc is a stable material and may be sterilized by heating at 160 C for not less
than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.
Talc should be stored in a well-closed container in a cool, dry place.

Page 33
 Drug and Excipient profile
LACTOSE Nonproprietary
Name: BP: Lactose
monohydrate.
Ph. Eur: Lactosum.
USP NF: Lactose monohydrate.
Synonyms: Fast-Flo; 4-(β-D-galactosido)-D-glucose; Lactochem; Microlose;
Milk sugar; Pharmatose; Saccharum lactis; Tablettose; Zeparox.
Chemical Name:
O-3-D-Galactopyranosyl-(1→4)-α-D-glucopyranose anhydrous. O-
3-D-Galactopyranosyl-(1→4)-α-D-glucopyranose monohydrous.
Description:
White to off-white crystalline particles or powder. Lactose is odorless and slightly sweet
tasting; α-lactose is approximately 15% as sweet as sucrose, while β-lactose is sweeter
than the α-form.

Properties:
Density: 1.540 for α-lactose monohydrate; 1.589 for anhydrous β-lactose.
Solubility: Practically insoluble in Chloroform, Ethanol, Ether and soluble in water.
Stability and Storage Conditions:
Under humid conditions (80% relative humidity and above), mold growth may
occur. Lactose may develop a brown coloration on storage, the reaction being accelerated
by warm, damp conditions. The purity of different lactoses can vary and color evaluation
may thus be important, particularly if white tablets are being formulated. The color
stability of various lactoses also differs. Saturated solutions ofβ-lactose may precipitate
crystals of α-lactose on standing. Lactose should be stored in a well-closed container in a
cool, dry, place.
Applications in Pharmaceutical Formulation or Technology
Anhydrous lactose is widely used in direct compression tableting applications, act
as tablet and capsule filler and binder. Anhydrous lactose can be used with moisture-
sensitive drugs due to its low moisture content. It may also be used in intravenous
injections.

Page 34
 AIMS AND OBJECTIVES

4. AIM AND OBJECTIVE

Famotidine is a second generation histamine H2 receptor antagonist . Famotidine

is used to treat gastric ulcers, duodenal ulcers, stomal ulcers, wounds in the lining of the
stomach associated with acute gastritis and with acute exacerbation of chronic gastritis.
The half-life following a single oral dose is 1.92 ± 0.94 h. The success of a therapy
depends on selection of the appropriate delivery system and the drug. Controlled release
dosage forms are designed to complement the pharmaceutical activity of a medicament in
order to achieve better selectivity and longer duration of action. Thus, Famotidine is
chosen as a suitable candidate for Gastric floating release drug delivery system. The aim
of the study was to design and evaluate floating drug delivery system of Famotidine
which may facilitate the following expectations.
 Improve the bioavailability of the drug.
 To increase the effectiveness in therapy.
 Reduction of dosing frequency.
 To improve patient compliance.
 To maintain plasma concentration of drug in therapeutic range for longer time.

The aim of the present study was to design and evaluate the FDDS of Famotidine with
following objectives.

 To formulate gastric floating tablet using excipients like HPMC k4m , Xanthan gum
HPMCK100,NaHCO3, etc for optimum deliver.
 To evaluate the powder mix for pre-compression characteristics and tablet
characteristics.
 To evaluate physical properties like hardness, friability, density etc. To evaluate
floating time of the formulation.
 To perform in vitro dissolution studies.

Page 35
 PLAN OF WORK

5. PLAN OF WORK

 Pre-formulation studies.

 Formulation of floating tablet by direct compression technique.

 Evaluation of formulated tablet for physical parameters like hardness,

thickness, diameter, friability, weight variation.

 In-vitro buoyancy.

o Buoyancy lag time.

o Duration of buoyancy.

 In-vitro drug release.

 Determination of in-vitro release kinetics.

Page 36
 MATERIALS AND METHODS
4MATERIALS AND METHODS
4.1 MATERIALS
4.1.1 Drugs & chemicals
The following materials of Pharma grade or the best possible Laboratory
Reagent (LR) were used as supplied by the manufacturer. The double distilled
water was used in all experiments.

Table 4.1 List of chemicals used with grade and supplier

Sr.
no. Materials used Grade supplier
Famotidine Spectrum Pharma labs
1. Pharma grade Hyderabad
Hydroxy propyl methyl
2. LR Spectrum Pharma labs
HPMC K100
3. LR Spectrum Pharma labs
4. Xanthan gum LR Shreeji chemicals, Mumbai
5. Avicel LR Shreeji chemicals, Mumbai
6. Sodium bicarbonate LR S.D fine chemicals, Mumbai

7. Lactose LR S.D fine chemicals, Mumbai

8. Mg-Stearate LR Shreeji chemicals, Mumbai

9. Talc LR Shreeji chemicals, Mumbai

Center drug house (p) Ltd,

10. Hydrochloric acid LR

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 MATERIALS AND METHODS
4.1.2. Instruments used for the preparation of Famotidine tablets.
able 4.2 List of instruments
Sr.
No. Instrument Manufacturer

1. U.V. visible spectrophotometer Shimadzu Corporation, Japan.

2. FTIR spectrophotometer IR-Affinity-1, Shimadzu, Japan.

3. Electronic balance Citizen scales Pvt. Ltd

4. Digital pH meter Digisun Electronics, Hyderabad

5. Bulk density apparatus Biological museum, Agra

6. Tablet punching machine Shakti, Ahmadabad

7. Roche friabilator Biological museum, Agra

8. Tablet hardness tester Pfizer

9. Digital caliper Aerospace

10. USP dissolution XXIII apparatus Electrolab TDL-08L

11. Hot air oven Universal

4.2 METHODS
4.2.1 Preformulation studies
It is one of the important prerequisites in development of any drug
delivery system. Preformulation studies of the drug were performed, which
included melting point determination, solubility and compatibility studies.

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 MATERIALS AND METHODS
Determination of melting point
Melting point of Famotidine was determined by capillary method. Fine
powder of Famotidine was filled in glass capillary tube (previously sealed on
one end). The capillary tube is tied to thermometer and placed in oil bath (light
paraffin oil bath), The temperature at which it starts to melt was noted.
Determination of λmax of Famotidine using 0.1 N HCL
A solution of Famotidine containing the concentration 10μg/ml was
prepared in 0.1 N HCL and UV spectrum was taken. The solution was scanned
in the range of 200-400nm.
Standard calibration curve of Famotidine using 0.1 N HCL Method
100 mg drug was accurately in 100ml volumetric flask. It was dissolved
in 0.1N HCL to gives 1000 μg /ml. the standard stock solution stock solution was
then serially diluted with 0.1 N HCL to get 1 to 10 μg/ml of Famotidine. The
absorbance was measured against 0.1 N HCL as blank at 279 nm using UV
spectrophotometer. The absorbance values were plotted against concentration
(μg/ml) to obtain the standard calibration curve.
Compatibility
Compatibility studies were performed through FTIR spectroscopy.
The IR spectrum of pure drug and physical mixture of drug and polymer was
studied. The characteristic absorption peaks of Famotidine obtained were
obtained at 4000-500cm-1.It has been observed that there is no
chemical interaction between Famotidine and polymer’s used. From the fig no
5.3, 5.4, 5.5, 5.6, & 5.7 it was observed that peak obtained in spectra drug an
polymers. which show there were no interaction between drug and polymers.

4.2.2 Pre-compression evaluation59

Angle of Repose
Angle of repose was determined by using funnel method. The blend was
poured through funnel that can be raised vertically until a maximum cone
height (h) was obtained. Radius of the heap (r) was measured and angle of
repose was calculated using the formula.

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 MATERIALS AND METHODS

Where, θ is the angle of repose, h is height of pile; r is radius of the base of pile.
Angle of Repose (ө) Flow
>25 Excellent
25-30 Good
30-40 Passable

Bulk Density
Apparent bulk density (ρb) was determined by pouring the blend into a
graduated cylinder. The bulk volume (Vb) and weight of powder (M) was
determined. The bulk density was calculated using the formula.

Tapped
Density
The measuring cylinder containing known mass of blend was tapped for a fixed
time. The minimum volume (Vt) occupied in the cylinder and weight (M) of the
blend was measured. The tapped density (ρb) was calculated using the
following formula

Carr’s compressibility index

The simplest way of measurement of free flow of powder is compressibility, an
indication of the ease with which a material can be induced to flow is given by
compressibility. The compressibility index of the granules was determined by
Carr’s compressibility index, which is calculated by using the following
formula

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 MATERIALS AND METHODS

% Compressibility Flow ability

5 – 12 Excellent
12 – 16 Good
18 – 21 Fair Passable
23 – 35 Poor
33 – 38 Very Poor
< 40 Very Very Poor

Hausner ratio
Hausner ratio is an indirect index of ease of powder flow. It is calculated by the
following formula

Where ρt is tapped density and ρd is bulk density. Lower Hausner ratio (< 1.25)

indicates better flow properties than higher ones

(>1.25).
4.2.3 Preparation of Famotidine floating
tablets By direct compression method
Famotidine floating was prepared by direct compression technique using drug
and variable concentration of polymers (HPMC K4M, HPMCK100, Xanthan
gum, Sodium Bicarbonate, MCC, Lactose, Mg-sterate, and Talc). The
respective powders & optional additives (composition listed in table-5.3) were
blended thoroughly with a mortar and pestle. The powder blended was then
lubricated with Mg-stearate and purified talc and then compressed on a tablet
punching machine.
4.2.4 Post-compression evaluation parameters for formulated
tablets a. Weight variation
Twenty tablets from each formulation were selected at random and average
weight was determined. Then the individual tablets were weighed and were
compared with average weight.
b. Hardness
The hardness of the tablet from each formulation was determined using

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 MATERIALS AND METHODS
Pfizer hardness tester.
c. Friability
Friability of the tablets was determined using Roche Friabilator. This device
subjects the tablets to the combined effect of abrasion and shock in a plastic
chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in
each revolution. Pre weighed sample of tablets was placed in the friabilator and
were subjected to 100 revolutions. Tablets were dedusted using a soft muslin
cloth and reweighed. The friability (f) is given by the formula.

Friability (f) = (1 - 100

Where, W0 is weight of the tablets before the test and W is the weight of the
tablet after the test.
d. Thickness and
diameter
The thickness and diameter of tablet was carried out using Digital caliper. Five
tablets were used for the above test from each batch and results were expressed
in millimeter.
e. Drug content
Powder one tablets extraction was carried out using 0.1 N HCL. The
concentration was determined spectrophotometrically against appropriate blank.
Calculate the content of Famotidine specific absorbance at 279 nm As given in
IP.
f.In-vitro buoyancy studies
The in vitro floating behavior of the tablets was studied by placing them in 100
ml beaker 100 ml of 0.1 N HCl (pH 1.2, 37 0C). The time, tablet required for
the emerge on the surface is floating lag time (FLT) or buoyancy lag time
(BLT). And the time tablet constantly float on the surface of the medium is
called total floating time (TFT).
g. In-vitro dissolution studies
The release rate of Famotidine from floating tablet was determined using the
United States Pharmacopoeia (USP) dissolution testing apparatus II. The
dissolution test was performed using 900ml of 0.1 N HCL, at 37 ± 0.5 0C and 50
rpm. The samples were taken at pre-selected time intervals with replacement of
equal volume of dissolution medium.

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5. RESULTS
5.1PREFORMULATION STUDIES
5.1.1 Determination of melting point
The melting point of Famotidine was found to be in range of 96 ~ 99 °C
5.2 ESTIMATION OF FAMOTIDINE BY UV SPECTROSCOPY
5.2.1Determination of lambda max

Fig: 5.1 UV Spectra of Famotidine at 10µg/ml concentration. Wavelength of maximum

absorption in 0.1N HCL solution was found to be 279nm.
5.2.2 Calibration curve
Table 5.1 Absorbance data for the calibration curve of Famotidine in 0.1N HCL
Sr. No. Concentration(µg/ml) Absorbance
1 0 0
2 2 0.07
3 4 0.133
4 6 0.204
5 8 0.270
6 10 0.340

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 CHAPTER 5 RESULTS

Absorbance

0.4 y = 0.0339x
R² = 0.9999
0.35
0.3
Absorbence 0.25
0.2 Absorbance
0.15 Linear (Absorbance)
0.1
0.05
0
0 5 10 15
concentretion (μg/ml)

Fig: 5.2 Standard calibration curve of Famotidine in 0.1N HCl

5.3 COMPATABILITY STUDIES
5.3.1 FTIR Spectroscopy
Identification of Famotidine
The IR spectrum of pure drug was found to be similar to the standard spectrum of
Famotidine.

Fig: 5.3 IR spectra of Famotidine.

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Fig: 5.4 IR spectra of MCC

Fig 5.5. FT-IR Spectra of Xanthan gum

Figure 5.6. FT-IR Spectra of HPMC K4M

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Figure 5.7. FT-IR Spectra of HPMC K100

Figure 5.8. FT-IR Spectra of Famotidine optimised formulation

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5.4 COMPOSITION OF FAMOTIDINE FLOATING TABLETS

Table 5.3 Composition of Famotidine floating tablet with FLT and TLT
Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
Drug 10 10 10 10 10 10 10 10 10 10 10 10
HPMC 25 30 35 20 20 20
HPMC 25 30 45 20 20 20
Xanthan 10 15 20 10 15 20 10 15 20 10 15 20
MCC q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s
NAHCO3 20 20 20 20 20 20 20 20 20 20 20 20
MG - 2 2 2 2 2 2 2 2 2 2 2 2
Talc 3 3 3 3 3 3 3 3 3 3 3 3
Lactose 50 45 35 50 45 35 45 50 50 45 50 40
Total wt 200 200 200 200 200 200 200 200 200 200 200 200
FLT 93 107 130 40 66 88 145 164 186 65 94 106
TFT (h) >12 >12 12 >12 >12 >12 >12 >12 12 >12 >12 12

5.5 PRE-COMPRESSION EVALUATION OF FAMOTIDINE FLOATING

TABLETS
Table 5.4 pre-compression parameters of Famotidine floating tablets
Tapped
Bulk density Hausner
Angle of density Carr index
Formulation (gm/cm ) ratio
repose (θ) (gm/cm ) (Ic) ±SD
code ±SD (HR)±SD
±SD ±SD
F1 22.21±0.825 0.224±0.010 0.262±0.011 1.129±0.006 11.423±0.511
F2 21.84±0.645 0.210±0.010 0.260±0.010 1.180±0.010 15.398±0.594
F3 22.96±0.471 0.227±0.010 0.266±0.005 1.173±0.005 15.002±0328.
F4 22.85±0.520 0.230±0.010 0.270±0.010 1.173±0.010 14.827±0.550
F5 22.46±0.471 0.225±0.020 0.260±0.010 1.150±0.060 15.792±0.357
F6 22.64±0.746 0.234±0.015 0.270±0.026 1.190±0.010 16.016±0.640
F7 23.64±0.312 0.220±0.005 0.282±0.011 1.207±0.004 17.676±0.732
F8 22.85±0.665 0.230±0.011 0.260±0.010 1.124±0.005 15.399±0.592
F9 21.54±0.346 0.220±0.010 0.266±0.015 1.190±0.010 15.397±0.594
F10 22.87±0.934 0.250±0.010 0.250±0.010 1.163±0.030 11.706±0.512
F11 22.43±0.726 0.230±0.011 0.260±0.010 1.180±0.010 16.676±0.560
F12 24.06±0.556 0.230±0.011 0.300±0.010 1.199±0.009 16.015±0.640
# All the values are expressed as mean ± SD. (n=3)

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POST COMPRESSION EVALUATION OF FAMOTIDINE FLOATING TABLETS

Table 5.5 Post-compression evaluation of Famotidine floating tablets
Formu Weight Hardness Diameter inThickness inFriability Drug
lation variation (Kg/cm2) (mm) (mm) (%)±SD content
code Average wt in±SD ±SD ±SD uniformity
(mg)±SD (%)±SD
F1 200.2± 0.952 4.932± 0.115 8.67± 0.577 2.129± 0.010 0.766± 0.090 96.362±0.305
F2 199.97± 0.877 4.863± 0.115 9.00± 0.000 2.239± 0.049 0.745± 0.060 98.738±0.228
F3 200.1± 0.857 4.946± 0.115 8.65± 0.577 2.253± 0.000 0.779± 0.017 98.432±0.355
F4 200.14± 0.815 4.644± 0.115 9.00± 0.000 2.204± 0.100 0.663± 0.010 94.513±0.130
F5 200.5± 0.885 4.943± 0.115 .32± 0.577 2.144± 0.066 0.592± 0.055 97.564±0.407
F6 195.6± 0.824 4.856± 0.115 9.65± 0.577 2.126± 0.055 0.759± 0.015 99.044±0.817
F7 200.15± 0.815 4.737± 0.115 8.65± 0.577 2.942± 0.057 0.663± 0.010 98.424±0.116
F8 200.04± 0.889 4.802± 0.200 8.67± 0.577 2.355± 0.100 0.782± 0.010 96.172±0.677
F9 200.12± 0.748 4.355± 0.208 9.34± 0.577 2.245± 0.057 0.756± 0.057 99.672±0.612
F10 200.2± 0.834 4.465± 0.115 8.67± 0.577 2.881± 0.052 0.769± 0.011 98.148±0.502
F11 199.58± 0.934 5.062± 0.155 9.00± 0.000 2.250± 0.000 0.671± 0.010 99.486±0.147
F12 200.3±0.833 4.801± 0.200 8.65± 0.577 2.279± 0.057 0.764± 0.011 98.592±0.391
# All the values are expressed as mean ± SD. (n=3)
5.7 IN-VITRO DRUG RELEASE STUDIES

5.7.1 In-vitro drug release data of Famotidine floating tablets

Table 5.6 In-vitro drug release data of Famotidine floating tablets of Batch F1 to F6
% Cumulative release
Time FT1±SD FT2±SD FT3±SD FT4±SD FT5±SD FT6±SD
1 9.276±0.438 8.000±0.150 7.899±0.88 16.985±0.219 15.052±0.207 10.043±0.174
2 15.478±0.305 15.606±0.306 13.138±0.262 26.900±0.182 24.953±0.218 18.912±0.328
3 18.530±0.133 17.210±0.393 17.629±0.349 29.057±0.304 27.274±0.393 26.637±0.262
4 26.754±0.219 22.358±0.307 16.124±0.231 35.836±0.264 35.117±0.315 36.466±0.267
5 33.838±0.217 26.395±0.353 25.419±0.267 48.825±0.134 44.039±0.353 38.545±0.282
6 35.962±0.278 35.857±0.413 29.327±0.364 53.772±0.349 52.943±0.348 49.082±0.200
7 47.114±0.218 38.709±0.354 35.877±0.308 66.424±0.305 59.637±0.307 59.034±0.307
8 48.987±0.267 45.925±0.365 46.513±0.354 74.421±0.258 68.269±0.309 67.108±0.393
9 59.648±0.183 52.638±0.395 57.518±0.355 75.991±0.524 74.878±0.352 68.340±0.307
10 68.467±0.218 65.236±0.350 62.096±0.269 87.379±0.200 83.945±0.396 77.404±0.256
11 75.267±182 73.736±0.174 69.861±0.267 85.351±0.534 87.733±0.262 83.953±0.958
12 82.346±0.182 78.812±0.135 75.624±0.219 96.083±0.457 91.542±0.782 88.812±0.314
# All the values are expressed as mean ± SD. (n=3)

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Table 5.7 In-vitro drug release data of Famotidine floating tablets of Batch F7 to F12
% Cumulative release
FT7±SD FT8±SD FT9±SD FT10±SD FT11±SD FT12±SD
1 10.831±0.352 8.872±0.172 7.474±0.455 12.323±0.0.447 11.322±0.219 10.625±0.532
2 16.998±0.0.266 11.997±0.328 12.328±0.412 18.331±0.437 15.622±0.397 16.824±0.742
3 24.017±0.352 18.878±0.220 17.341±0.353 28.774±0.744 24.466±0.485 21.058±0.653
4 33.898±0.393 19.618±0.306 21.623±0.307 38.457±0.524 32.158±0.353 27.949±0.698
5 38.828±0.315 23.146±0.399 25.634±0.532 49.716±0.659 43.154±0.439 35.747±0.618
6 45.856±0.353 29.388±0.347 33.853±0.534 58.581±0.656 47.343±0.448 46.248±0.661
7 55.835±0.348 37.172±0.394 39.282±0.332 69.471±0.568 54.060±0.573 55.865±0.662
8 60.689±0.308 44.951±0.353 49.630±0.367 72.428±0.632 64.934±0.513 63.201±0.746
9 67.741±0.352 55.434±0.308 56.568±0.355 78.508±0.228 73.164±0.581 67.382±0.702
10 75.842±0.306 67.828±0.351 64.488±0.397 83.304±0.402 76.211±0.397 73.515±0.747
11 79.132±0.353 74.582±0.308 75.404±0.315 87.488±0.444 82.343±0.415 78.396±0.704
12 88.621±0.414 82.356±0.306 79.521±0.423 92.354±0.864 85.624±0.367 83.731±0.537
# All the values are expressed as mean ± SD. (n=3)

100

90
%
CUMULATIVE 80
DRUG
RELEASE
70

60

50

40

30

20

10

TIME
.
Fig: 5.9 In-vitro drug release profile of Famotidine floating tablets of batches F1 to F12.

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5.8 DRUG RELEASE KINETICS OF FAMOTIDINE

5.8.1 Zero order release kinetics
Table 5.8 Zero order kinetics data of Famotidine floating tablets of Batch F1 to F6
% Cumulative release
Time FT1±SD FT2±SD FT3±SD FT4±SD FT5±SD FT6±SD
1 9.272±0.438 8.000±0.150 7.899±0.88 16.985±0.219 15.052±0.207 10.043±0.174
2 15.478±0.305 14.604±0.306 13.138±0.262 26.900±0.182 24.953±0.218 18.912±0.328
3 17.530±0.133 17.210±0.393 16.629±0.349 28.057±0.304 27.274±0.393 26.637±0.262
4 26.754±0.219 23.358±0.307 16.124±0.231 35.836±0.264 34.117±0.315 35.466±0.267
5 33.838±0.217 26.395±0.353 23.419±0.267 48.825±0.134 44.039±0.353 38.545±0.282
6 35.962±0.278 35.857±0.413 29.327±0.364 53.772±0.349 52.943±0.348 49.082±0.200
7 46.114±0.218 39.708±0.354 35.877±0.308 65.424±0.305 57.637±0.307 58.034±0.307
8 47.987±0.267 45.925±0.365 45.513±0.354 74.421±0.258 68.269±0.309 67.108±0.393
9 59.648±0.183 52.638±0.395 57.518±0.355 75.991±0.524 74.878±0.352 68.340±0.307
10 69.467±0.218 65.236±0.350 62.096±0.269 86.379±0.200 83.945±0.396 79.404±0.256
11 75.267±182 72.736±0.174 67.861±0.267 85.351±0.534 87.733±0.262 83.953±0.958
12 82.356±0.182 79.812±0.135 75.624±0.219 95.083±0.457 91.542±0.782 88.812±0.314
#All values are expressed as mean ±SD. (n=3)

Table 5.9 Zero order kinetics data of Famotidine floating tablets of Batch F7 to F12
% Cumulative release
Time
FT7±SD FT8±SD FT9±SD FT10±SD FT11±SD FT12±SD
1 10.831±0.352 8.872±0.172 7.474±0.455 12.323±0.447 11.322±0.219 10.625±0.532
2 17.998±0.266 11.997±0.328 11.328±0.412 19.331±0.437 15.622±0.397 15.824±0.742
3 24.017±0.352 16.878±0.220 17.341±0.353 28.774±0.744 23.466±0.485 21.058±0.653
4 31.898±0.393 19.618±0.306 21.623±0.307 38.457±0.524 32.158±0.353 27.949±0.698
5 38.828±0.315 23.146±0.399 26.634±0.532 49.716±0.659 41.154±0.439 35.747±0.618
6 45.856±0.353 28.388±0.347 33.853±0.534 58.581±0.656 47.343±0.448 46.248±0.661
7 52.835±0.348 37.172±0.394 39.282±0.332 66.471±0.568 54.060±0.573 55.865±0.662
8 60.689±0.308 44.951±0.353 48.630±0.367 72.428±0.632 64.934±0.513 61.201±0.746
9 67.741±0.352 55.434±0.308 56.568±0.355 78.508±0.228 70.164±0.581 67.382±0.702
10 73.842±0.306 66.828±0.351 64.488±0.397 82.304±0.402 76.211±0.397 73.515±0.747
11 79.132±0.353 74.582±0.308 74.404±0.315 87.488±0.444 82.343±0.415 78.396±0.704
12 88.621±0.414 82.356±0.306 79.521±0.423 92.354±0.864 85.624±0.367 83.731±0.537
#All values are expressed as mean ±SD. (n=3)

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FT1
100 FT2
90 FT3
Cumulative
%drug release 80 FT4
70
FT5
60
FT6
50
FT7
40
30 FT8
20 FT9
10 FT10
0 FT11
0 5 10 15
FT12
Time (hrs)

Fig: 5.10 Zero order release profile of Famotidine floating tablets of batches F1 to F12

5.8.2First order release kinetics data of Famotidine floating tablets

Table 5.10 First order release kinetics of Famotidine of Batch F1 to F6
Log % Cumulative release
Time
FT1±SD FT2±SD FT3±SD FT4±SD FT5±SD FT6±SD
1 1.961 1.964 1.969 1.928 1.928 1.948
2 1.943 1.947 1.949 1.893 1.893 1.918
3 1.917 1.929 1.932 1.850 1.856 1.876
4 1.883 1.902 1.914 1.800 1.813 1.828
5 1.847 1.860 1.896 1.748 1.756 1.782
6 1.805 1.834 1.862 1.675 1.690 1.716
7 1.763 1.788 1.794 1.575 1.606 1.634
8 1.698 1.740 1.752 1.486 1.488 1.555
9 1.617 1.667 1.695 1.380 1.434 1.487
10 1.513 1.566 1.612 1.220 1.303 1.390
11 1.394 1.452 1.508 1.028 1.123 1.257
12 1.270 1.327 1.390 0.772 0.915 1.053

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 CHAPTER RESULT
5 S

Table 5.11 First order release kinetics of Famotidine of Batch F7 to F12

Log % Cumulative release to remain to release
Time
FT7±SD FT8±SD FT9±SD FT10±SD FT11±SD FT12±SD
1 1.950 1.958 1.967 1.94306 1.949 1.952
2 1.918 1.948 1.943 1.912048 1.922 1.930
3 1.887 1.925 1.913 1.858699 1.879 1.903
4 1.838 1.910 1.889 1.796186 1.826 1.864
5 1.792 1.892 1.858 1.70999 1.777 1.815
6 1.742 1.862 1.814 1.627965 1.728 1.739
7 1.683 1.806 1.775 1.538188 1.653 1.655
8 1.606 1.749 1.703 1.455955 1.558 1.598
9 1.522 1.659 1.628 1.352002 1.488 1.527
10 1.434 1.534 1.538 1.271722 1.395 1.438
11 1.338 1.422 1.425 1.13067 1.248 1.314
12 1.058 1.246 1.313 0.864959 1.150 1.210

2.5 FT1
FT2
2 FT3
Log%remaining
to release FT4
1.5 FT5
FT6

1 FT7
FT8

0.5 FT9
FT10
FT11
0
0 5 10 15 FT12

Time (hrs)

Fig: 5.11 First order release profile of Famotidine floating tablets of batches F1 to F12.

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5.8.3 HIGUCHI RELEASE KINETICS DATA OF FAMOTIDINE FLOATING TABLETS

Table 5.12 Higuchi release kinetics data of Famotidine of Batch F1 to F6
Root % Cumulative release
Time FT1±SD FT2±SD FT3±SD FT4±SD FT5±SD FT6±SD
1.00 9.272±0.438 8.000±0.150 7.899±0.88 16.985±0.219 15.052±0.207 10.043±0.174
1.41 15.478±0.305 14.604±0.306 13.138±0.262 26.900±0.182 24.953±0.218 18.912±0.328
1.73 17.530±0.133 17.210±0.393 16.629±0.349 28.057±0.304 27.274±0.393 26.637±0.262
2.00 26.754±0.219 23.358±0.307 16.124±0.231 35.836±0.264 34.117±0.315 35.466±0.267
2.23 33.838±0.217 26.395±0.353 23.419±0.267 48.825±0.134 44.039±0.353 38.545±0.282
2.44 35.962±0.278 35.857±0.413 29.327±0.364 53.772±0.349 52.943±0.348 49.082±0.200
2.64 46.114±0.218 39.708±0.354 35.877±0.308 65.424±0.305 57.637±0.307 58.034±0.307
2.82 47.987±0.267 45.925±0.365 45.513±0.354 74.421±0.258 68.269±0.309 67.108±0.393
3.00 59.648±0.183 52.638±0.395 57.518±0.355 75.991±0.524 74.878±0.352 68.340±0.307
3.16 69.467±0.218 65.236±0.350 62.096±0.269 86.379±0.200 83.945±0.396 79.404±0.256
3.31 75.267±182 72.736±0.174 67.861±0.267 85.351±0.534 87.733±0.262 83.953±0.958
3.46 82.356±0.182 79.812±0.135 75.624±0.219 95.083±0.457 91.542±0.782 88.812±0.314
#All values are expressed as mean ±SD. (n=3)

Table 5.13 Higuchi release kinetics data of Famotidine of Batch F7 to F12

Root % Cumulative release to remain to release
Time FT7±SD FT8±SD FT9±SD FT10±SD FT11±SD FT12±SD
1.00 10.831±0.352 8.872±0.172 7.474±0.455 12.323±0.447 11.322±0.219 10.625±0.532
1.41 17.998±0.266 11.997±0.328 11.328±0.412 19.331±0.437 15.622±0.397 15.824±0.742
1.73 24.017±0.352 16.878±0.220 17.341±0.353 28.774±0.744 23.466±0.485 21.058±0.653
2.00 31.898±0.393 19.618±0.306 21.623±0.307 38.457±0.524 32.158±0.353 27.949±0.698
2.23 38.828±0.315 23.146±0.399 26.634±0.532 49.716±0.659 41.154±0.439 35.747±0.618
2.44 45.856±0.353 28.388±0.347 33.853±0.534 58.581±0.656 47.343±0.448 46.248±0.661
2.64 52.835±0.348 37.172±0.394 39.282±0.332 66.471±0.568 54.060±0.573 55.865±0.662
2.82 60.689±0.308 44.951±0.353 48.630±0.367 72.428±0.632 64.934±0.513 61.201±0.746
3.00 67.741±0.352 55.434±0.308 56.568±0.355 78.508±0.228 70.164±0.581 67.382±0.702
3.16 73.842±0.306 66.828±0.351 64.488±0.397 82.304±0.402 76.211±0.397 73.515±0.747
3.31 79.132±0.353 74.582±0.308 74.404±0.315 87.488±0.444 82.343±0.415 78.396±0.704
3.46 88.621±0.414 82.356±0.306 79.521±0.423 92.354±0.864 85.624±0.367 83.731±0.537
#All values are expressed as mean ±SD. (n=3)

[Type text] Page 52

 CHAPTER 5 RESULTS

FT1

100 FT2
release

90 FT3
70 FT5
80 FT4
to

60 FT6
%remaini
Log

50
ng

FT7
40
FT8
30
FT9
20
FT10
10
0 FT11
0 1 2 3 4 FT12
Time(hrs)

.
Fig: 5.12 Higuchi release kinetics profile of Famotidine floating tablets of batches F1 to
F12.

5.8.4 Peppas Release Kinetics Data of Famotidine Floating Tablets

Table 5.14 Peppas release kinetics data of Famotidine floating tablets of Batch F1 to F6
Log Log % Cumulative release
Time FT1±SD FT2±SD FT3±S FT4±SD FT5±SD FT6±SD
0.00 0.916 0.904 0.843 1.176 1.178 1.042
0.301 1.094 1.063 1.047 1.340 1.342 1.229
0.477 1.242 1.183 1.166 1.462 1.452 1.392
0.602 1.374 1.309 1.259 1.567 1.544 1.512
0.698 1.474 1.438 1.330 1.642 1.634 1.598
0.778 1.553 1.504 1.437 1.723 1.706 1.682
0.845 1.623 1.588 1.579 1.796 1.774 1.757
0.903 1.697 1.653 1.637 1.842 1.840 1.807
0.954 1.769 1.728 1.702 1.880 1.861 1.840
1.00 1.828 1.800 1.772 1.922 1.903 1.878
1.041 1.877 1.854 1.832 1.952 1.937 1.914
1.079 1.910 1.897 1.878 1.974 1.963 1.948

[Type text] Page 53

 CHAPTER 5 RESULTS

Table 5.15 Peppas release kinetics data of Famotidine floating tablets of Batch F7 to F12
Log Log % Cumulative release to remain to release
Time FT7±SD FT8±SD FT9±SD FT10±SD FT11±SD FT12±SD
0.00 1.034 0.948 0.874 1.088 1.050 1.024
0.301 1.230 1.042 1.090 1.264 1.221 1.170
0.477 1.363 1.042 1.264 1.444 1.389 1.303
0.602 1.488 1.268 1.355 1.574 1.520 1.432
0.698 1.578 1.346 1.442 1.688 1.604 1.540
0.778 1.652 1.438 1.543 1.760 1.666 1.656
0.845 1.715 1.559 1.604 1.817 1.740 1.738
0.903 1.776 1.643 1.696 1.854 1.806 1.778
0.954 1.825 1.734 1.760 1.888 1.838 1.823
1.00 1.863 1.819 1.817 1.912 1.877 1.860
1.041 1.893 1.867 1.866 1.937 1.916 1.898
1.079 1.948 1.916 1.900 1.967 1.934 1.924

Log %remainimg to 2.5 FT1

release FT2
2 FT3
FT4
1.5 FT5
FT6
1 FT7
FT8
0.5 FT9
FT10
0 FT11
0 0.2 0.4 0.6 0.8 1 1.2 FT12

Time(hrs)
.
Fig: 5.13 Peppas release kinetics profile of Famotidine floating tablets of batches F1 to F12.

[Type text] Page 54

 CHAPTER 5 RESULTS

5.8.5 Different Drug Release Kinetics Model For Famotidine Floating Tablets
Table 5.16 Regression coefficients fit to different drug release kinetics models for
Famotidine floating tablets.
Formulation Zero order First order Higuchi Peppas
code r2 r2 r2 r2 n
F1 0.917 0.942 0.910 0.974 0.904
F2 0.985 0.902 0.865 0.970 0.969
F3 0.977 0.990 0.848 0.963 0.993
F4 0.994 0.916 0.952 0.990 0.780
F5 0.992 0.930 0.951 0.989 0.767
F6 0.995 0.943 0.940 0.995 0.878
F7 0.997 0.916 0.930 0.994 0.867
F8 0.960 0.857 0.818 0.928 0.956
F9 0.992 0.922 0.885 0.986 0.979
F10 0.983 0.955 0.956 0.990 0.863
F11 0.996 0.958 0.942 0.994 0.865
F12 0.995 0.959 0.922 0.978 0.910

[Type text] Page 55

 [Type the document title]

5.8.6 In-vitro buoyancy studies of the Famotidine floating tablet

Fig 5.15 In-vitro buoyancy studies of

Fig 5.14 In-vitro buoyancy studies of
the Famotidine floating tablet using
the Famotidine floating tablet using
HPMC K100 (F4) At (41 sec)
HPMC K4M (F1) At (92 sec)

Fig 5.16 In-vitro buoyancy studies of the

Famotidine floating tablet using HPMC Fig 5.17 In-vitro buoyancy studies of the
K100 & Xanthangum(F7). At (144 sec) Famotidine floating tablet using HPMC
K4M& Xathangum(F10). At (67 sec)

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 Discussion

6. DISCUSSION
In the present study, Gastroretentive floating drug delivery systems of
Famotidine were prepared by using different viscosity grades of hydroxy propyl methyl
cellulose (HPMC), K4M and Sodiumalginate, and Xanthan gum at different drug to
polymer ratios with gas generating agent like sodium bicarbonate.
The weighed quantities of drug and polymers were mixed thoroughly in
different ratios and tablets were prepared by direct compression method. The prepared
tablets were evaluated for its hardness, friability, uniformity of weight, uniformity of drug
content, drug-polymer interaction studies, in vitro floating studies, in-vitro dissolution
studies.
Preformulation studies:
Determination of melting point
The melting point of Famotidine was found to be 96 ~ 99 °C, which complied
with BP standards thus indicating purity of obtained drug sample.
Determination of lambda (λ) max of Famotidine
On the basis of preliminary identification test it was concluded that the
Famotidine complied the preliminary identification. By scanning the drug in U.V
spectrophotometer in 200-400 nm range, a sharp peak was observed at 279 nm using 0.1
N HCL as solvent. It was concluded that the drug has λmax 279 nm (as per I.P) as
showed in fig 5.1

Preparation of standard calibration curve of Famotidine

From the standard curve of Famotidine it was observed that the drug obeys
Beer’s law in the range 2-20 µg/ml and the equation was generated it was showed fig 5.2
and table 5.1.
Drug-polymer interaction study
The drug-polymer interaction study was carried out using FTIR (KBr pellet
method)
FTIR
FTIR drug-polymers interaction studies are shown in fig 5.3 to 5.7 . It was found
that Famotidine was compatible with HPMC K4M, Sodiumalginate, and Xanthan gum,
used in the formulation, there were no extra peaks observed. Thus the chosen

Page 57
 Discussion

polymers for the formulations were found to be compatible with Famotidine and have no
physical interaction.
Pre-compression Evaluation parameters
The angle of repose of the drug powder was in the range of 21.54 to 24.06, the
Carr’s index was found to be in the range of 11.42 to 17.67 indicating compressibility of
the tablet. Haunser’s ratio was found in the range of 1.12 to 1.20 is good as reported in
table 5.4.
Post-compression parameters
• Weight variation
Prepared tablets were evaluated for weight variation and percentage deviations
from the average weight are reported in table 5.5.and was found to be within the
prescribed official limits.
• Friability
The friability of the formulations as found to be between 0.59 to 0.78 is reported
in table 5.5 and as that of which was found to be within the official requirement (i.e. not
more than 1%).
• Tablet thickness and hardness
The thickness of the tablet indicates that die fill was uniform. The thickness
depends upon the size of the punch and the weight of the tablet (200 mg). The thickness
of the batch from F1-F12 was found to be 2.12-2.94 mm and hardness was found to be
4.3-5.0 Kg/cm2 as reported in table 5.5 which had good mechanical strength.
• Drug content uniformity
The Percentage of drug content for F1 to F12 was found to 94.513±0.130 to
99.672±0.612 of Famotidine, it complies with official specifications. The results were
shown in table 5.5.
• In-vitro buoyancy study
0
On immersion in 0.1 N HCL solution pH (1.2) at 37 C, the tablets floated, and
remained buoyant without disintegration. Fig 5.14 to 5.17 shows Buoyancy character of
prepared tablet. From the results it can be concluded that the batch containing HPMC
K4M polymer showed good floating lag time (FLT). Formulation containing HPMC
K4M, Sodiumalginate showed less FLT compare to formulation containing Xantha

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 Discussion
In-vitro dissolution studies
In-vitro dissolution studies were performed for all the batches of tablets
containing Famotidine using USP XXIII dissolution test apparatus-II at 50rpm, 900ml of
0.1N HCl used as dissolution media. The In-vitro drug release data was given in tables
5.6 to 5.16 and drug release profiles are shown in fig 5.9 to 5.13.
Formulations F1, F2 and F3 containing drug and HPMC K4M exhibited 82.356±0.182,
79.812±0.135 and 75.624±0.219 of drug release 12 hours respectively and the data is
given in table 5.6 and drug release profiles are shown in fig 5.9
Formulations F4, F5 and F6 containing drug polymer Sodiumalginate, exhibited
95.083±0.457, 91.542±0.782 and 88.812±0.314 of drug release in 12 hours respectively
and the data is given in table 5.6 and drug release profiles are shown in fig 5.9.

Formulations F7, F8 and F9 containing drug and polymers like Sodiumalginate and
Xanthan gum exhibited 88.621±0.414, 82.356±0.306 and 79.521±0.423 of drug release in
12 hours respectively and the data is given in table 5.7 and drug release profiles are
shown in fig 5.9
Formulations F10, F11 and F12 containing drug and polymers like HPMC K4M and
Xanthan gum exhibited 92.354±0.864, 85.624±0.367 and 83.731 ±0.537 of drug release
in 12 hours respectively and the data is given in table 5.7 and drug release profiles are
shown in fig 5.9 respectively.
Drug release kinetics: The in-vitro drug release data was subjected to analysis according
to zero order, first order kinetic equations,
Higuchi and Peppas models to ascertain the mechanism of drug release. The
results of linear regression analysis of data including regression coefficient are
summarized in table 5.16.
When the regression coefficient ‘r’ value of zero order and first order plots were
compared, it was observed that the ‘r’ values of zero order were in the range of 0.917 to
0.997 whereas the ‘r’ values of first order plots were found to be in the range of 0.857 to
0.990 indicating drug release from all the formulations were found to follow zero order
kinetics.
The Higuchi’s plot has shown with the regression values in the range of 0.818 to

Page 59
 Discussion
0.952 shown in table no 5.12 and 5.13
The in-vitro dissolution data as log cum percent drug release versus log time were fitted
to Peppas, values of the exponent ‘n’ was found to be in the range of 0.767 to 0.993
indicating that the drug release is by Non-Fickian diffusion mechanism.

Page 60
 CONCLUSION

7. CONCLUSION

From the compatibility studies, it is concluded that , HPMC K4M,

Xanthangum ,HPMCK100,were compatible with drug Famotidine and thus suitable
for the formulation of Famotidine floating tablets.
Famotidine tablets were fabricated by direct compression method. In-vitro
buoyancy studies were performed for all the formulations, F1 to F12 by using 0.1 N
HCL solution at 370C. Tablet containing HPMC (F4) showed good buoyancy with
very short lag time and long floatation time of more than 12 hrs in 0.1 N HCL. In-
Vitro release study is performed for 12 hrs. Optimized formula containing
HPMCK100 (F4) showed better release compare to other formulations and it followed
zero order kinetics. The non-Fickian diffusion was confirmed as the drug release
mechanism from this formulation.

From this study, it was concluded that HPMCK100 can be used in formulation of
Lafutidin esustained release gastro retentive floating drug delivery system. Overall,
this study concludes that viscosity of the polymer is a major factor affecting the drug
release and floating properties of FDDS.
SCOPE FOR THE FUTURE STUDIES:
The principle of FDDS can be adopted for drug acting locally in stomach.
The work can be extended to the In-vivo studies to conclude In-vitro and In- vivo
correlation.
Work can be extended to the In-vivo buoyancy studies in humans.
The formulation of FDDS can be tried with different grades of HPMC and other
swellable polymers.
The work can be carried out to study the effect of other response parameters like
bioadhesiveness, etc, on floating and release rate of drug.
The work can be carried out to improve the physical stability of the dosage form
like coating the tablet.

Page 61
 summary

8. SUMMARY

The present study is an attempt to develop floating tablets of Famotidine, with

different polymers which releases a therapeutic amount of Famotidine to the proper site

in the body and also to achieve and maintain the desired Famotidine concentration.

Direct compression method was used for formulation of floating tablets, also

different types of polymers like HPMC K4M, HPMCK100, Xanthangum were studied.

These polymers were widely used gel forming polymers. The release rate could

effectively be modified by varying the “polymer” concentration. By using HPMCK100

they gave optimum FLT as well as long acting effect. It was found that the tablet

formulation retarded the drug release for 12h as desired.

The results of the drug-excipients compatibility by FTIR studies revealed that

there was no chemical interaction between the pure drug and excipients. The

Precompression parameters like bulk density, tapped density, Carr’s index and angle of

repose were determined. The final formulation showed acceptable flow properties. The

post compression parameters like the thickness, hardness, friability, weight variation,

content uniformity, FLT and TFT and In vitro release, were carried out and the values

were found to be within IP limits.

Thus it is summarized and concluded that HPMCK100can be successfully used

in formulation of Famotidine sustained release gastroretentive floating tablets.

Page 62
 BIBLIOGRAPHY

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