M.pharm thesis

FORMULATION AND EVALUATION OF GASTRO-
RETENTIVE MUCOADHESIVE MICROBALLONS OF
NIZATIDINE FOR MANAGEMENT OF PEPTIC ULCER
Dissertation Part-II report submitted to
RAJIV GANDHI PROUDYOGIKI VISHWAVIDYALAYA, BHOPAL (M.P.)
For the partial fulfillment of the degree of
MASTER OF PHARMACY
Pharmaceutics
Supervised by
Dr.SarangJain
Principal
Submitted by
PARMANAND DHAKAD
Enroll.no 0148PY16MP09
Co-GUIDE
Ms. Swati Saxena
Associate Professor
RAJEEV GANDHI COLLEGE OF PHARMACY,BHOPAL
SESSION2020-2021

RAJEEV GANDHI COLLEGE OF PHARMACY
Village: Salaiya, Via Danish Kunj, Kolar Road, Bhopal
Department of Pharmaceutics
CERTIFICATE
This is to certify that the dissertation entitled “FORMULATION AND EVALUATION
OF GASTRO-RETENTIVE MUCOADHESIVE MICROBALLONS OF
NIZATIDINE FOR MANAGEMENT OF
PEPTIC ULCER” submitted to Rajiv Gandhi Proudyogiki Vishwavidhyalaya, Bhopal
by Mr. Parmanand Dhakad is a partial fulfillment of the requirement for the award of
the degree of the M.Pharm. with specialization in Pharmaceutics. The matter embodied
is the actual work by Mr. Parmanand Dhakad and this work has not been submitted
earlier in part or full for the award of any otherdegree.
PARMANAND DHAKAD
Enroll. No. 0148PY16MP09
Dr. Sarang Jain
Principal
Ms. Swati Saxena
Associate Professor

BHOPAL
DECLARATION
I hereby declare that the work, which is being presented in the dissertation, entitled
“FORMULATION AND EVALUATION OF GASTRO- RETENTIVE
MUCOADHESIVE MICROBALLONS OF NIZATIDINE FOR MANAGEMENT
OF PEPTIC ULCER” submitted
by Mr. Parmanand Dhakad (0148PY16MP09) for the award of degree of “Master of
Pharmacy” degree with specialization in Pharmaceutics, comprises of bonafide research
work carried out by me in our laboratories, library and computer centre under the
guidance of Dr. Sarang Jain, Principal and Ms Swati Saxena, Associate Professor.,
Department of Pharmaceutics, Rajeev Gandhi College of Pharmacy, Bhopal.
I also declare that the present work embodies has not formed the basis for the award of
any other degree or fellowship previously. The particulars given in this thesis are to best
of myknowledge.
Date
Place: Bhopal
PARMANAND DHAKAD

BHOPAL
DECLARATION
I hereby declare that the work, which is being presented in the dissertation, entitled
“Formulation And Evaluation of Gastro-retentive Mucoadhesive Microballons of
Nizatidine For Management of Peptic Ulcer” partial fulfillment of the requirements
for the award of degree of Master of Pharmacy in Pharmaceutics submitted in the
department of Pharmaceutics (Rajeev Gandhi College of Pharmacy, Bhopal M.P.) is an
authentic record of my own work carried under the guidance of Dr.Sarang Jain and Ms
Swati Saxena. I have not submitted the matter embodiedin this report for award of any
otherdegree.
I also declare that “A check for Plagiarism has been carried out on the thesis/ project
report/ dissertation and is found within the acceptable limit and report of which is
enclosed herewith.”
Name of Student
PARMANAND DHAKAD
Name of Supervisor
Dr. Sarang Jain
Principal
Name of Co-Supervisor
Ms. Swati Saxena
Associate Professor

ACKNOWLEDGEMENT
Firstly, I offer my adoration to God who created me, gave me the strength
and courage to complete my dissertation and gave me the opportunity to thank all those
people through whom his Grace was delivered to me.
With a deep sense of gratitude, I express my indebtedness to my guide, Dr.
Sarang Jain, Principal Rajeev Gandhi college of Pharmacy, Bhopal, for his valuable
guidance, boundless enthusiasm and constant inspiration throughout the entire course of
the work. I shall forever remain indebted to his for having inculcated in me a quest for
excellence, a spirit of diligenceIt is my privilege to express my heartfelt thanks to my Co-
guide Ms Swati Saxena, Department of Pharmaceutics, for her guidance and
encouragement throughout the research work.
I sincerely thank all the teaching staff and non-teaching staff, Mr Navneet
Dube, Mr Anuj Singhai, Mr. Bajpei, Mr.Pradeep and librarian Mr. Dharmendra. It
gives me immense pleasure to record my sincere thanks to my colleagues friends& Non
collegeous friends Risabh mishra, Sumit Raikwar, Nidhi Malviya ,and for their help and
co- operation.
I sincerely acknowledge the authorities of Rajeev Gandhi college of
Pharmacy, Bhopal, for providing the necessary facilities to carry out my research
work. I would like to thank all those who have helped me directly or indirectly to
complete this work successfully.
From deepest depth of my heart, I express my love and gratitude to my
beloved parents Mr Raghuraj Singh Dhakad , Mrs. Shusila Bai and all family members
for their love, support and constant encouragement throughout my career.
Thank you one & all
Date
Place: Bhopal
PARMANAND DHAKAD

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" FORMULATION AND EVALUATION OF GASTRO-
RETENTIVE MUCOADHESIVE MICROBALLONS OF
NIZATIDINE FOR
MR.
MANAGEMENT OF PEPTIC ULCER”
PARMANAND DHAKAD
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CONTENT
Chapter Title Page no.
1 INTRODUCTION 1-24
1.1 Peptic ulcer 1
1.2 Drug Delivery System 6
1.3 Gastro-retentive drug delivery system 9
1.4 Mechanism of Bioadhesion 15
1.5 Mucoadhesive Microspheres 23
2 REVIEW OF LITERATURE 25-48
2.1 Drug profile 25
2.2 Excipients review 26
2.3 Literature review 39
3 PLAN OF WORK & HYPOTHESIS 49-50
3.1 Objective 49
3.2 Hypothesis 49
3.3 Plan of present work 49
4 MATERIAL AND METHODS 51-59
4.1 Analytical and Validation studies 51
4.2. Preformulation Studies 52
4.2.1 Organoleptic properties 52
4.2.2 Microscopic examination 52
4.2.3 Physical Characteristics 52
4.3 Preparation of mucoadhesive Microballons 55
4.4 Evaluation of mucoadhesive microballons 57

5 RESULT AND DISCUSSION 60-60
5.1 Analytical and Preformulation studies of model drug 60
5.2 Preformulation Studies 61
5.3 Evaluation of mucoadhesive microspheres 65
6 Summary and conclusion 81-82
7 References 83-67

LIST OF TABLES
Table
No.
Particulars Page No.
1.1 Routes of drug administration and dosage form / drug delivery systems 6
1.2 Different theories explaining the mechanism of bioadhesion 15
1.3 Bioadhesive strength of some polymers 21
1.4 Application of Bioadhesive Systems 22
1.5 Patents related to bioadhesive system 23
4.1 Drug-excipient combinations for compatibility study 55
4.2 Preparation of of mucoadhesive microballons of Nizatidine HCl (A1 – B3) 56
5.1 Organoleptic characteristics of Nizatidine HCl 62
5.2 Flow properties of drug (n = 3) 62
5.3 The solubility of Nizatidine HCl at different pH medium (n=3) 62
5.4 Drug-excipient combinations for compatibility study 63
5.5 Results of physical observation 63
5.6 Results of content determination 63
5.7
Percentage yield of mucoadhesive microballons of Nizatidine HCl (A1 –
B3)
67
5.8 Particle size of mucoadhesive microballons of Nizatidine HCl (A1 – B3) 67
5.9
Drug entrapment efficiency of mucoadhesive microballons of Nizatidine
HCl (A1 – B3)
68
5.10
Degree of swelling of mucoadhesive microballons of Nizatidine HCl (A1 –
B3)
68
5.11
Percent mucoadhesion of mucoadhesive microballons of Nizatidine HCl
(A1 – B3)
69
5.12 Buoyancy test of mucoadhesive microballons of Nizatidine HCl (A1 – B3) 70

5.13
LIST OF FIGURES
70
Dissolution data of mucoadhesive microballons of Nizatidine HCl (A1 –B3)
5.14 in-vitro dissolution data of mucoadhesive microballons of Nizatidine HCl
(A1)
71
5.15
in-vitro dissolution data of mucoadhesive microballons of Nizatidine HCl
(A2)
72
5.16
(CH1)
73
5.17
(CH2)
74
5.18
(CA1)
75
5.19
(CA2)
76
5.20
(B1)
77
5.21
(B2)
78
5.22
(B3)
79

Figure
No.
Particulars Page No.
1.1
(a) Microspheres floats on stomach contents. (b & c) microspheres adhere
to stomach wall
14
1.2 Three regions within a mucoadhesive joint 16
2.1 Structure of drug Nizatidine 25
2.2 Chemical structure of microcrystalline cellulose 27
2.3 Chemical structure of anhydrous lactose 29
2.4 Chemical structure of sodium starch glycolate 30
2.5 Chemical structure of starch 32
2.6 Chemical structure of guar gum 35
2.7 Chemical structure of cellulose hydroxypropyl methyl ether 38
5.1
Absorption maxima (λ-max) of Nizatidine HCl in 0.1N HCl solution (10
μg/ml)
60
5.2 Standard curve of Nizatidine HCl in 0.1N HCl solution (228 nm) 61
5.3 The I. R. Spectrum of sample of pure Nizatidine HCl (S1) 64
5.4 The I. R. Spectrum of sample of Nizatidine HCl and all excipients (S2) 64
5.5 Photograph of microspheres (100X) 66
5.6 SEM photomicrograph of microspheres (650X) 66
5.7
Zero-order plots for mucoadhesive microballons of Nizatidine HCl (A1 –
B3)
80
5.8
First-order plots for for mucoadhesive microballons of Nizatidine HCl (A1
– B3)
80

FORMULATION AND EVALUATION OF GASTRO-RETENTIVE MUCOADHESIVE MICROBALLONS OF NIZATIDINE
FOR MANAGEMENT OF PEPTIC ULCER
Page 1
1: INTRODUCTION
Peptic Ulcer
Drug Delivery System
Gastro-retentive Drug Delivery System
Mechanism of Bioadhesion
PEPTIC ULCER
Peptic ulcer occurs in that part of the gastrointestinal tract (g.i.t.) which is exposed to
gastric acid and pepsin, i.e. the stomach and duodenum. The etiology of peptic ulcer is
not clearly known. It results probably due to an imbalance between the aggressive (acid,
pepsin, bile and H. pylori) and the defensive (gastric mucus and bicarbonate secretion,
prostaglandins, nitric oxide, high mucosal blood flow, innate resistance of the mucosal
cells) factors. A variety of psychosomatic, humoral and vascular derangements have been
implicated and the importance of Helicobacter pylori infection as a contributor to ulcer
formation and recurrence has been recognized. In gastric ulcer, generally acid secretion is
normal or low, while deficient mucosal defence (mostly impaired mucus and bicarbonate
secretion) plays a greater role. In duodenal ulcer, acid secretion is high in about half of
the patients but normal in the rest. Notwithstanding whether production of acid is normal
or high, it does contribute to ulceration as an aggressive factor, reduction of which is the
main approach to ulcer treatment. An understanding of the mechanism and control of
gastric acid secretion will elucidate the targets of antisecretory drugaction.
An ulcer is a round or oval shaped hole (also called parietal defect), 2 to 4 cm in
diameter with perpendicular borders and a smooth base. A Peptic Ulcer is an ulcer in the
gastrointestinal tract that is characteristically acidic and thus extremely painful. It is also
called ulcers pepticum or peptic ulcer disease (PUD). Contrary to general belief peptic
ulcers happen more often in the duodenum first part of the small intestine than in the
stomach. Duodenal ulcers are usually benign whereas about 4% of stomach ulcers are
caused by a malignant tumor. The borders of the Peptic ulcer are not well-known in the
acute form but elevated and inflammatory in the chronic form. In the ulcerative form of

Page 2
Heartburn
gastric cancer the borders are uneven. Due to parietal scarring the surrounding mucosa
(inner mucus lining) may come into view.
Types of Peptic ulcer
Peptic Ulcers are categorized by their site in the body:
Gastric Ulcer – in the stomach
Duodenal Ulcer – in the duodenum (the first part of the small intestine)
Esophageal Ulcer – in the esophagus
Meckel’s Diverticulum Ulcer – a small pouch in the wall at the junction
of the small and large intestines
Prepyloric Ulcer – between inner and outer walls of the stomach
Proximal gastroesophageal Ulcer – in the mucosa, submucosa, and
muscular layer on the lower esophagus, stomach, or duodenum to have
radial folds.
Symptoms of Peptic Ulcer
A patient with Peptic Ulcer would have some of the next symptoms
Bloating of the abdomen
Waterbrash – this is the rush of saliva in the mouth after an incident of
regurgitation in order to dilute the acid in the esophagus
Abdominal pain – duodenal ulcers are characteristically relieved by foodwhile
gastric ulcers are exacerbated by it
Nausea and a lot of vomiting
Loss of appetite
Weight loss
Hematemesis – vomiting of blood due to gastric ulcer or injure to esophagus from
frequent vomiting

Page 3
Melena – tarry foul-smelling feces due to oxidized iron from the hemoglobin
Gastric or duodenal perforation (in some severe cases).
The timing of the symptoms in relation to meals may distinguish between gastric
and duodenal ulcers. In the gastric ulcer, the ache would be during or after meals
because the alkaline duodenal contents reflux into the stomach. In duodenal
ulcers the ache would manifest before a meal when acid manufacturing increases
due to hunger and is passed into the duodenum. However, this is not used as a
dependable method of diagnosis.
Causes of Peptic Ulcer
In most cases, tobacco smoking, anorexia (malnutrition), blood group, spicy food
and other factors that were suspected to source ulcers until late in the 20th century, are
actually of minor importance in the development of peptic ulcers. But these are factors
that make worse the symptoms of peptic ulcer, once formed. Some of the causes are:
Bacteria: As much as 60% of gastric and up to 90% of duodenal ulcers are linked with
Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic surroundings of the
stomach. This bacterium colonies the antral mucosa (inner mucus lining) and grows
rapidly. The antibodies are not capable to clear the infection. This causes localized
erosion and damage of the mucosa and results in ulcer formation.
Reaction to medications: Ulcers can also be sourced or worsened by drugs such as
aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Normally,
prostaglandins kindle the secretion of mucus in the gastrointestinal tract to defend its
inner lining from gastric acid. NSAIDs block this function and the risk of ulceration
increases. Hence, peptic ulcer due to reaction to medication is found additional in aged
people suffering from arthritis or those with pain syndromes. Ulcerogenesis can also be
caused by making use of glucocorticoids.
Tobacco: Smoking leads to atherosclerosis and vascular spasms. This guides to ischemia
(localized reduction of blood flow) and ulcers.

Page 4
Heredity: A family history is often there in duodenal ulcers, especially when blood
group O is also present. But studies show that this is not a significant factor in the case of
gastric ulcers.
Zollinger Ellison syndrome: Gastrinomas, rare gastrin-secreting tumors cause multiple
ulcers which are hard to heal.
Diagnosis of Peptic Ulcer
Endoscopy: Esophagogastroduodenoscopy (EGD), a form of endoscopy, also
recognized as a gastroscopy, is carried out on patients in whom a peptic ulcer is
supposed. By direct visual identification, the location and harshness of an ulcer
can be diagnosed. Moreover, if no ulcer is there, EGD can often give an
alternative diagnosis. In patients over 45 years with more than two weeks of the
above symptoms, the odds for peptic ulceration are high sufficient to warrant
rapid investigation by EGD.
Findings of endoscopy: The microscopical emergence of the ulcer shows 4
zones: inflammatory exudate (fluid); fibrinoid necrosis dead cells; granulation
tissue; and fibrous tissue. The fibrous base of the ulcer may hold vessels with
thickened wall or with thrombosis (formation of blood clot).
Urea breath test: This is a non-invasive test and does not need an endoscopy.
Blood test: This is just to ensure for the presence of antibodies but is not a
sufficient diagnostic method for Peptic ulcer.
Stool antigen test: This is a non-invasive immunoassay to identify active
infection with Helicobacter pylori bacteria in fecal samples.
Histological examination: The possibility of other causes of ulcers, notably
malignancy (gastric cancer) needs to be reserved in mind. This is especially true
in ulcers of the greater (large) curvature of the stomach.
X-ray: This is carried out to rule out perforated Peptic Ulcer. If the air leaks from
the gastrointestinal tract (which contains air) to the peritoneal cavity (which never
contains air), there would be free gas within the peritoneal cavity. The gas will

Page 5
drift to a position underneath the diaphragm and a chest X-ray would illustrate an
erect chest and supine, lateral abdomen. This is a sure signal of perforated peptic
ulcer and should be treated forthwith.
Treatment of Peptic Ulcer
Antacids: Young, otherwise fit patients with ulcer-like symptoms are treated with
antacids or H2 antagonists before Endoscopy (EGD) is undertaken. Bismuth
compounds may in fact reduce or even clear organisms and no further treatment is
required.
Antibiotics: When Helicobacter pylori infection is there, the most effective
treatments are mixtures of any two antibiotics like Clarithromycin, Amoxicillin,
Tetracycline or Metronidazole along with a proton pump inhibitor (PPI) and a
bismuth compound.
Surgery: Perforated peptic ulcer becomes a surgical emergency and requires
surgical mend of the perforation. Most bleeding ulcers need endoscopy urgently
to stop the bleeding with cautery destroying abnormal tissue by burning with
electrosurgery or with injection
Prevention of Peptic Ulcer
There is no proven way to stop peptic ulcer disease (PUD) but some measure
can be taken to decrease the risk:
Reduce use of NSAIDs: Use of non-steroidal anti-inflammatory drugs (NSAIDs)
appears to grounds ulcers by inhibiting the body’s production of prostaglandins,
hormones that defend the stomach lining. Patients should also be prescribed a
prostaglandin analogue in order to help stop peptic ulcers.
Tested for Helicobacter pylori: If a person has a family history of ulcers being
tested for disease by Helicobacter pylori bacterium can be a preventivemeasure
Quit smoking: Smokers are about twice as likely to extend ulcers as non-smokers
as they are more vulnerable to Helicobacter pylori, and provide more favorable
conditions for the bacteria to thrive and diminish gastric mucosaldefenses.

Page 6
Reduce stress: There’s conflicting evidence that pressure is one of the causes of
peptic ulcer and more so in duodenal ulcers. But relaxation exercises like yoga;
meditation; and other stress-reducing strategies can assist decrease blood pressure
and slow heart rate more as a general wellness practice.
Stop alcohol: Alcohol aggravates formation and uneasiness from ulcers although
it does not reason it 1
.
Drug Delivery System
The drug-delivery system should deliver drug at a rate dictated by the needs of the
body over a specified period of time. The goal of any drug delivery system is to provide a
therapeutic amount of drug to a proper site in the body, so that the desired drug
concentration can be achieved promptly and then maintained. The idealized objective
points to the two aspects most important to drug delivery, namely, spatial placement and
temporal delivery. Spatial placement relates to targeting drugs to specific organs, tissues,
cells, or even subcellular compartments; whereas temporal delivery refers to controlling
the rate of drug delivery to the target site 2,3
.
The various routes of drug administration and dosage forms 4
are shown in Table 1.
Table 1.1: Routes of drug administration and dosage form / drug deliverysystems
S. NO. TERM SITE PRIMARY DOSAGE
FORM
1 Oral Mouth Tablets, Capsules, Solutions,
Syrups, Elixirs, Suspensions,
Magmas, Gels, Powders
Peroral
(per os: to be
swalled)
Gastrointestinal
tract via mouth
2 Sublingual Under the tongue Tablets, Troches or Lozenges
3 Parenteral Other than the
gastrointestinal
tract (by
Solutions, Suspensions

Page 7
injection)
Interavenous Vein
Interaarterial Artery
Interacardiac Heart
Interaspinal or
Interathecal
Spine
Interaosseous Bone
Interaarticular Joint
Interasynovial Joint-fluid area
Interacutaneous
or Interadermal
Skin
Subcutaneous Beneath the skin
Interamuscular Muscle
4 Epicutaneous
(Topical)
Skin surface Ointments, Creams,
Infusion pumps, Pastes,
Plasters, Powders,Aerosols,
Lotions, Transdermal patches,
Transdermal discs,
Transdermal solutions
5 Transdermal Skin surface
6 Conjunctival Conjunctiva Contact lenses inserts,
Ointments
7 Intraocular Eye Solutions, Suspensions
8 Intranasal Nose Solutions, Sprays,
Inhalants, Ointments
9 Aural Ear Solutions

Page 8
Minimize or eliminate local side effects
10 Intrarepiratory Lung Aerosols
11 Rectal Rectum Solutions,
Ointments, Suppositories
12 Vaginal Vagina Solutions, Ointments,
Emulsion foams, Tablets,
Inserts, Suppositories, Sponge
13 Urethral Urethra Solutions, Suppositories
: Several types of modified-release drug products are recognized:
1.2.1.1: Extended-release drug products:
A dosage form that allows at least a twofold reduction in dosage frequency as
compared to that drug presented as an immediate-release (conventional) dosage form.
Examples of extended-release dosage forms include controlled-release, sustained-release,
and long-acting drug products5, 6
.
: Delayed-release drug products:
A dosage form that releases a discrete portion or portions of drug at a time or at
times other than promptly after administration, although one portion may be released
promptly after administration. Enteric-coated dosage forms are the most common
delayed-release products.
: Targeted-release drug products:
A dosage form that releases drug at or near the intended physiologic site of action.
Targeted-release dosage forms may have either immediate- or extended-release
characteristics 6, 7
.
: Advantages of modified drug therapy: 6
1. Avoid patient compliance problems
2. Employ less total drug

Page 9
Minimize or eliminate systematic side effects
Obtain less potentiation or reduction in drug activity with chronic use
Minimize drug accumulation with chronic dosing
3. Improve efficiency in treatment
Cure and control condition more promptly
Improve control of condition (i.e., reduce fluctuation in drug level)
Improve bioavailability of somedrugs
4. Economic savings
Gastro-retentive drug delivery system:
Even though various drug delivery systems are used for maximizing therapeutic index
and reduction in the side effects of the drug, oral route remains the preferred, promising
and effective route for the administration of therapeutic agents. Because, low cost of
therapy, ease of administration, flexibility in formulation and handling leads to higher
level of patient compliance. Approximately 50% of the drug delivery systems available in
the market are oral drug delivery system 8
.
The novel design of an oral controlled drug delivery system during last two decades, it
has limited success in case of drugs with a poor absorption window throughout the GIT
(Gastro Intestinal Tract). This approach has several physiological difficulties such as
inability to restrain and locate the controlled drug delivery system within the desired
region of the gastrointestinal tract (GIT) due to variable gastric emptying and motility.
Furthermore, the relatively brief gastric emptying time in humans which normally
averages 2-3 h through the major absorption zone, i.e., stomach and upper part of the
intestine can result in incomplete drug release from the drug delivery system leading to
reduced efficacy of the administered dose 9
Advantages of GRDDs
1. Floating dosage forms such as tablets or capsules will remains in the solutionfor
prolonged time even at the alkaline pH of the intestine

Page 10
2. FDDS are advantageous for drugs meant for local action in the stomach eg:
antacids
3. FDDS dosage forms are advantageous in case of vigorous intestinal movement
and in diarrhea to keep the drug in floating condition in stomach to get a relatively
better response.
4. Acidic substance like aspirin causes irritation on the stomach wall when come in
contact with it hence; HBS/FDDS formulations may be useful for the
administration of aspirin and other similar drugs.
5. The FDDS are advantageous for drugs absorbed through the stomach eg: Ferrous
salts, Antacids 10-12
.
Disadvantages of GRDDs
1. Floating systems are not feasible for those drugs that have solubility or stability
problems in gastric fluids.
2. Drugs such as Nifedipine, which is well absorbed along the entire GI tract and
which undergo significant first pass metabolism, may not be suitable candidates
for FDDS.
3. One of the disadvantages of floating systems is that they require a sufficiently
high level of fluids in the stomach, so that the drug dosage form float therein and
work efficiently.
4. These systems also require the presence of food to delay their gastric emptying 13-
14
.
Potential drug candidates for gastro retentive drug delivery Systems
1. Drugs those are locally active in the stomach e.g misoprostol, antacids etc.
2. Drugs that have narrow absorption window in gastrointestinal tract (GIT) e.g. L-
DOPA, para-aminobenzoic acid, furosemide, riboflavin etc.
3. Drugs those are unstable in the intestinal or colonic environment e.g.captopril,
ranitidine HCl,
4. Drugs that disturb normal colonic microbes e.g.antibiotics against Helicobacter
pylori.

Page 11
5. Drugs that exhibit low solubility at high pH values e.g. diazepam,
chlordiazepoxide,
6. verapamil HCl.
Drugs those are unsuitable for gastroretentive drug delivery systems
1. Drugs that have very limited acid solubility e.g. phenytoin etc.
2. Drugs that suffer instability in the gastric environment e.g. erythromycin etc.
3. Drugs intended for selective release in the colon. eg. 5- amino salicylic acid and
corticosteroids etc.15
.
Polymers and other ingredients used for the preparations of Floating drugs
i) Polymers: The following polymers used to preparations of floating drugs: HPMC K4
M, Calcium alginate, Eudragit S100 Eudragit RL, Propylene foam, Eudragit RS, ethyl
cellulose, poly methyl methacrylate, Methocel K4M, Polyethylene oxide, %
Cyclodextrin, HPMC 4000, HPMC 100, CMC, Polyethylene glycol, polycarbonate, PVA,
Polycarbonate, Sodium alginate, HPC-L, HPC, Eudragit S, HPMC, Metolose S.M. 100,
PVP, HPCH, HPC-M, HPMC K15, Polyox, HPMC K4, Acrylic polymer E4 M and
Carbopol.
ii) 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,
Gelucires® 39/01 and 43/01.
iii) Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-
Sodium Glycine Carbonate, CG (Citroglycine).
iv) Release rate accelerants (5 - 60%): lactose, mannitol.
v) Release rate retardants (5 - 60%): Dicalcium phosphate, talc, magnesium stearate
vi) Buoyancy increasing agents (upto 80%): Ethyl cellulose
vii) Low density material: Polypropylene foam powder (Accurel MP 1000®) 11-15
.

Page 12
Approaches to GRDDS
To formulate a successful stomach specific or gastroretentive drug several techniques are
currently used such as
Hydrodynamically balanced systems 17
Bioadhesive or Mucoadhesive 18
Raft systems incorporating alginate gels 19-22
Modified shape systems 19
High density systems 20-23
Swelling system 24-26
Magnetic systems 26-27
Floating drug delivery 28-29
Colloidal gel barrier system
Microporous compartment system
Alginate beads 30
Hollow microspheres / Microballons 31
Effervescent systems
Drug release from effervescent (gas generating) systems
This system can also be further described as:
(i) Volatile liquid containing systems 37
(ii) Gas-generating Systems
Among these the following have been studied extensively.
Floating drug delivery systems
Non effervescent systems
Gas generating systems
High density systems
Bioadhesive system

Page 13
Floating system
Drug delivery system that float immediately upon contact with gastric fluids
present promising approach for increasing the bioavailability of drugs with absorption
window in the upper small intestine. However, immediate floating can only be achieved
if the density of the device is low at the very beginning. Devices with an initially high
density (which decreases with time) first settle down in the stomach and thus undergo the
risk of premature emptying. Inherent low density can, for example, be provided by the
entrapment of air (e.g. hollow chambers) or by the (additional) incorporation of low
density materials e.g. fatty substances or oils or foampowder.
Non effervescent systems
This type of system, after swallowing, swells unrestrained via imbibition 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.
Gas generating systems
These buoyant systems utilise matrices prepared with swellable polymers like
methocel, polysaccharides like chitosan and effervescent components like sodium
bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at
body temperature.
The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas
generation is reported to be 0.76:1. The common approach for preparing these systems
involves resin beads loaded with bicarbonate and coated with ethylcellulose. The coating,
which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is
released, causing the beads to float in the stomach.

Page 14
High density systems
Sedimentation has been employed as a retention mechanism for pellets that are
small enough to be retained in the rugae or folds of the stomach body near the pyloric
region, which is the part of the organ with the lowest position in an upright posture.
Dense pellets (approximately 3g/cm3
) trapped in rugae also tend to withstand the
peristaltic movements of the stomach wall. With pellets, the GI transit time can be
extended from an average of 5.8 to 25 hours, depending more on density than on
diameter of the pellets, although many conflicting reports stating otherwise also found in
the literature. Commonly used excipients are barium sulphate, zinc oxide, titanium
dioxide and iron powder, etc. These materials increase density by up to 1.5–2.4g/cm3
.
However, no successful system has reached the market.
Figure 1.1. (a) microspheres floats on stomach contents. (b & c)
microspheres adhere to stomach wall
Bioadhesive drug delivery systems
Bioadhesive drug delivery systems (BDDS) are used to localize a delivery device
within the lumen to enhance the 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. A microbalance-based system is reported for measuring the forces of interaction
between the GI mucosa and the individual polymers. The Cahn Dynamic Contact Angle
Analyzer has been used to study the adherence.
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

Page 15
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 polycarbophil,
carbopol, lectins, chitosan, CMC and gliadin, etc. Some investigators have tried out a
synergistic approach between floating and bioadhesion systems.
The major challenge for bioadhesive drug delivery systems is the high turnover
rate of the gastric mucus and the resulting limited retention times. Furthermore, it is
difficult to target specifically the gastric mucus with bioadhesive polymers. Most of
the latter (e.g. polycarbophil, Carbopol and chitosan) will stick to various other
surfaces that they come into contact with. In addition; the possibility of oesophageal
binding might present a challenge regarding safety aspects.
Mechanism of Bioadhesion
The mechanism of adhesion of polymers to mucosal tissues has involved both
chemical and physical binding. Both weak and strong interactions (i.e. Vander walls
interaction, hydrogen bonding and ionic bonding) can develop between certain types of
chemical groups on the polymer (i.e. –OH, -COOH) and the glycoprotein network of the
mucus layer or the glycoprotein chains attached to the epithelial cells.
Mucous membranes
Mucous membranes (mucosae) are the moist surfaces lining the walls of various
body cavities such as the gastrointestinal and respiratory tracts. They consist of a
connective tissue layer (the lamina propria) above which is an epithelial layer, the surface
of which is made moist usually by the presence of a mucus layer. The epithelia may be
either single layered (e.g. the stomach, small and large intestine and bronchi) or
multilayered/stratified (e.g. in the oesophagus, vagina and cornea). The former contain
goblet cells which secrete mucus directly onto the epithelial surfaces, the latter contain,
or are adjacent to tissues containing, specialised glands such as salivary glands that
secrete mucus onto the epithelial surface. Mucus is present as either a gel layer adherent
to the mucosal surface or as a luminal soluble or suspended form. The major components
of all mucus gels are mucin glycoproteins, lipids, inorganic salts and water, the latter
accounting for more than 95% of its weight, making it a highly hydrated system. The

Page 16
mucin glycoproteins are the most important structure-forming component of the mucus
gel resulting in its characteristic gel-like, cohesive and adhesive properties. The thickness
of this mucus layer varies on different mucosal surfaces, from 50 to 450 µm in the
stomach to less than 1 µm in the oral cavity. The major functions of mucus are that of
protection and lubrication (they could be said to act as anti-adherents).
Figure 1.2. Three regions within a mucoadhesive joint
Mucoadhesives
The most widely investigated group of mucoadhesives is hydrophilic
macromolecules containing numerous hydrogen bond forming groups, the so-called first
generation mucoadhesives. Their initial use as mucoadhesives was in denture fixative
powders or pastes. The presence of hydroxyl, carboxyl or amine groups on the molecules
favours adhesion. They are called the wet adhesives in that they are activated by
moistening and will adhere non-specifically to many surfaces. Once activated, they will
show stronger adhesion to dry inert surfaces than those covered with mucus. Unless water
uptake is restricted, they may over hydrate to form slippery mucilage. Like typical
hydrocolloid glues, if the formed adhesive joint is allowed to dry then, they can form
very strong adhesive bonds. Typical examples are carbomers, chitosan, sodium alginate
and the cellulose derivatives.
Mucoadhesive / Mucosa Interaction
For adhesion to occur, molecules must bond across the interface. These bonds can
arise in the following way
Ionic bonds—where two oppositely charged ions attract each other via
electrostatic interactions to form a strong bond (e.g. in a salt crystal).
Covalent bonds—where electrons are shared, in pairs, between the bonded
atoms in order to fill the orbital in both. These are also strong bonds.

Page 17
Hydrogen bonds—here a hydrogen atom, when covalently bonded to
electronegative atoms such as oxygen, fluorine or nitrogen, carries a slight
positively charge and is therefore is attracted to other electronegative atoms. The
hydrogen can therefore be thought of as being shared, and the bond formed is
generally weaker than ionic or covalent bonds.
Vander-Waals bonds—these are some of the weakest forms of interaction that
arise from dipole–dipole and dipole-induced dipole attractions in polar
molecules, and dispersion forces with non-polar substances.
Hydrophobic bonds—more accurately described as the hydrophobic effect,
these are indirect bonds (such groups only appear to be attracted to each other)
that occur when non-polar groups are present in an aqueous solution. Water
molecules adjacent to non-polar groups form hydrogen bonded structures, which
lowers the system entropy.
Table 1.2: Different theories explaining the mechanism of bioadhesion
S. No. Theory Mechanism of bioadhesion
1 Electronic theory Attractive electrostatic forces between glycoprotein
mucin network and the bioadhesive material.
2 Adsorption theory Surfaces forces resulting in chemical bonding.
3 Wetting theory Ability of bioadhesive polymers to spread and develop
intimate contact with the mucus membranes.
4 Diffusion theory Physical entanglement of mucin strands and the flexible
polymer chains. Interpretation of mucin strands into the
porous structure of the polymer substrate.
5 Fracture theory Analyses the maximum tensile stress developed during
detachment of the BDDS from the mucosal surfaces.

Page 18
Factors Affecting Mucoadhesion
Polymer related factors
Molecular weight Low molecular weight polymer favors the inter
penetration of polymer molecules, high molecular
weight polymer favours physical entanglement.
Flexibility of polymer chains Required for interpenetration and entanglement.
Highly cross-linked polymers: mobility of
individual polymer chains decreases which leads
to decreased bioadhesive strength.
Concentration of polymer Solid BDDS: more is the polymer concentration
higher is the bioadhesive strength, Liquid BDDS:
optimum concentration is required for best
bioadhesion, High concentration may result in
coiling of polymer molecules and hence reduced
flexibility of the polymeric chains.
Methods to Study Bioadhesion
In-vitro methods for testing bioadhesion for the design and development of
bioadhesive controlled release systems and to ensure compatibility, physical and
mechanical stability of these systems (Peppas et al., 1985). These methods include:
i. Ex vivo methods : Methods based on measurement of tensile strength
or shear strength.
Adhesion weight method
Fluorescent probe method
Mechanical spectroscopic method
Falling liquid film method
Flow channel method
Colloidal gold staining method

Page 19
Viscometric method
Thumb test
Adhesion number
Electrical Conduction
ii. In vivo methods
Use of radioisotopes
Use of gamma scintiography
Advantages and Limitations of Mucoadhesive Drug Delivery System
Mucoadhesive dosage forms have following advantages because of their property to
immobilize drug-carrying particles at the mucosal surface.
A prolonged residence time at the site of action or absorption thus permit onceor
twice a day dosing.
Increase in drug concentration gradient due to the intimate contact of the particles with
the mucosal surface.
Adirect contact with mucus membrane, which is the step earlier to particle absorption.
Bioadhesive system can prevent the first pass metabolism to certain protein drugs by
the liver through the introduction of the drugs via route bypassing the digestive tract.
Drugs that are absorbed through mucosal lining of tissues can enter directly into the
blood stream and prevented from enzymatic degradation in the GIT.
These dosage forms facilitate intimate contact of the formulation with the
underlying absorption surface. This allows modification of tissue permeability for
absorption of macromolecules such as peptides and proteins, inclusion of
penetration enhancers such as Sodium glycolate, Lysophosphatidylcholine, Sodium
taurocholate and Protease inhibitors in the mucoadhesive dosage forms resulted in
the better absorption of peptides/ proteins.

Page 20
Limitations
Gastric mucoadhesion does not tend to be strong enough to impart to dosage forms
the ability to resist the strong propulsion forces of the stomachwall.
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 seems to limit the potential of mucoadhesion as a gastro-retentiveforce.
Mucoadhesive Polymers
There are two broad classes of mucoadhesive polymers: water-soluble and/or
water insoluble polymers, having swellable networks, joined by cross-linking agents. In
large classes of hydrophillic polymers those containing carboxylic group exhibit the best
bioadhesive properties, Polyvinyl pyrrolidone, Methylcellulose, Sodiumcarboxy
methylcellulose, Hydroxypropyl cellulose and other cellulose derivatives.
Hydrogel are the class of polymeric biomaterial that exhibit the basic
characteristics of an hydrogel to swell by absorbing water interacting by means of
adhesion with the mucus that covers epithelia (Junginger et al., 1990) i.e.
Anionic group - Polyacrylates and their cross-linked modifications
Cationic group - Chitosan (Hango, 1998) and its derivatives
Neutral group - Eudragit-NE30D etc.
The polymer should possess optimal polarity to make sure that it is sufficiently
wetted by the mucus and optimal fluidity that permits the mutual adsorption.
An ideal mucoadhesive polymer should have following characteristics:
The polymer and its degradation products should be nontoxic, nonabsorbable
It should be non-irritant to the mucous membrane
Itshouldforma strongnoncovalent bondwiththe mucinepithelialcellsurfaces
It shouldadherequicklytomoisttissueandshouldpossesssomesitespecificity
The cost of the polymer should not be high

Page 21
Thepolymermustnotdecomposeonstorageorduringshelflifeofthedosageform
It should allow easy incorporation of the drug and offers no hindrance to its
release.
Bioadhesive Strength of Some Polymers Table
1.3: Bioadhesive strength of some polymers
S. No. Polymer name Bioadhesive property
1 Polycarbophil +++
2 Tragacanth +++
3 Poly (acrylic acid/ divinyl benzene) +++
4 Sodium alginate +++
5 Carbopol 934 +++
6 Carboxymethyl cellulose
CMC (low viscosity) ++
CMC (high viscosity) +
CMC (medium viscosity) +
7 Hydroxyethyl cellulose +++
8 Gum karaya ++
9 Guar gum ++
10 Chitosan ++
11 Pectin +
12 Gelatin +
13 Thermally modified starch +
14 Hydroxyethyl methacrylate +
15 Amberlite–200 resin +

Page 22
16 Hydroxypropyl cellulose +
17 Polyethylene glycol +
18 Polyvinyl pyrrolidone +
19 Chitosan (Dr. Knapczyk) +
20 Daichitosan H ++
+++ Excellent (8.0 to 12.0 mN/cm2
); ++ fair (1.5 to 8.0 mN/cm2
);+ poor (<1.5mN/cm2
).
Application of Bioadhesive Systems
Table 1.4: Application of Bioadhesive Systems
Drug Route of
administration
Polymer used Comment
Acyclovir Ocular Chitosan Slow release rate,
increased AUC
Gentamycin Nasal DSM+LPC Slow release rate
Insulin Nasal DSM+LPC Efficient delivery into
systemic circulation
via nasal route
Furosemide GI AD-MMS[PGEFs] Increased bioavailability
Amoxicillin GI AD-MMS[PGEFs] Greater H-pylori activity
Vancomycin Colonic PGEF coated with
Eudragit S 100
Well absorb even with
enhancer
Insulin Colonic PGEF coated with
Eudragit S 100
Absorbtion only in
presence of enhancer
Methyl
perdisolone
Ocular Hyaluronic acid Slow release rate

Page 23
1.4.10 Patents Related to Bioadhesive Systems
Table 1.5: Patents related to bioadhesive system 32
Patent
number
Assignee/Inventor Year Title
US
6368586
Brown University Research
foundation
April
2002
Methods and compositions
for enhancing bioadhesive
properties of polymers
WO
0203955
Roversi Francesco, Cilurzo
Francesco
Jan.
2002
Fast release bioadhesive
microspheres for the
sublingual administration of
Proximate
US
627415
Immunex Corporation Aug
2001
Prolonged release of GM-CSF
US
6207197
West Pharmaceutical
Services Drug Delivery and
Clinical Research Centre
March
2001
Gastroretentive controlled
release microspheres
Mucoadhesive Microballons:
Microballons are small spherical particles, with diameters in the micrometer range
(typically 1µm to 1000µm or 1mm). Microballons are sometimes referred to as
microparticles. Microballons are defined as “the monolithic spheres or therapeutic agents
distributed throughout the matrix either as a molecular dispersion of particles”.
Microballons are small spherical particles with diameter in the micrometer range
and sometimes referred as microparticles. When adhesion is restricted to the
mucous layer lining of the mucosal surface it is termed as mucoadhesion.
Mucoadhesion offers prolonged residence time at the site of absorption,
localization of the drug delivery system at a given target site, increase in drug

Page 24
concentration gradient due to the intestine contact of the particle with the
mucosal surface. Development of adhesive bond between polymer and biological
membrane or its coating can be achieved by two ways: initial contact between the
surfaces or formation of secondary bonds due to non covalent interaction.
Mucoadhesives must interact with mucin layer during the process of attachment.
Mucins are synthesized by globet cells and special exocrine glands with mucin
cells acnini. There are atleast two main targets which could be used for anchoring
of delivery system through mucoadhesive in the GIT, the mucosal tissue and
mucosal gel layer. The mucos layer is the first surface encountered by particulate
system and its complex structure offers many opportunities for the
development of adhesive interaction with small polymeric particles either through
non specific or specific interaction between complimentary structures. Due to all
above advantages Microsphere delivery is an better choice for drug delivery in
colon 33
.

Page 25
2: REVIEW OF LITERATURE
: DRUG PROFILE:
NIZATIDINE
Structure:
Figure 2.1: Structure of drug Nizatidine
Chemical name: N-[2-[[2-(dimethylaminomethyl)-1,3-thiazol-4-
yl]methylsulfanyl]ethyl]-N'-methyl-2-nitroethene-1,1-diamine
Molecular formula:
Molecular weight :
C12H21N5O2S2
331.5
Physical characteristics: A white to off–white crystalline solid.
Melting range:
Storage:
130-132ºC
Store in air tight, temper proof container, protected
from light.
Mechanism of action: Nizatidine is a competitive, reversible inhibitor of histamine at
the histamine H2 receptors, particularly those in the gastric parietal cells. By inhibiting
the action of histamine on stomach cells, nizatidine reduces stomach acid production.
Nizatidine competes with histamine for binding at the H2-receptors on the gastric
basolateral membrane of parietal cells. Competitive inhibitionresults
basal and nocturnal gastric acid secretions. The drug also decreases
in reduction of
the gastric acid
response to stimuli such as food, caffeine, insulin, betazole, or pentagastrin.
Plasma half life: 1.5 hrs

Page 26
Disposition in the body: Nizatidine is readily and almost completely absorbed after oral
administration and peak plasma concentrations are reached within 1 to 3 h. Absorption is
increased by the presence of food and decreased by 10% in the presence of antacids such
as aluminium hydroxide gel and magnesium silicate. It is partially metabolised by the
liver, but does not inhibit the hepatic mixed function oxidase system. Three metabolites
have been identified, nizatidine N-2–oxide, nizatidine S-oxide and N-2–mono des methyl
nizatidine (60% activity of nizatidine). Nizatidine is widely distributed throughout the
body and has been detected in breast milk (0.1% of the administered dose). 90% of an
administered dose is excreted in urine, partly by active tubular secretion, with 60% as the
unchanged drug. Less than 6% of a dose is excreted in faeces.
Protein binding: 35%.
Dose: Orally the usual daily dose is 150 to 600 mg. The total intravenous daily dose
should not exceed 480 mg.
Pharmacokinetics parameter: Volume of distribution: Approx. 1.2 to 1.6 L/kg (single
150 mg dose), 1.1 to 1.9 L/kg (multiple doses). Clearance: Serum 37.5 to 41.4 L/h (single
150 mg dose), 39.1 to 44.6 L/h (multiple doses). Plasma 40 to 51 L/h.
Side effects: It include an allergic reaction (difficulty in breathing, closing of throat)
bleeding gums, irregular heartbeat, fever or yellowing of the skin or eyes, headache,
dizziness or diarrhea may occur 34
.
: EXCIPIENTS REVIEW
Cellulose, microcrystalline
Nonproprietary Names: BP: Microcrystalline cellulose, JP: Microcrystalline cellulose,
PhEur: Cellulosum microcristallinum, USPNF: Microcrystalline cellulose
Synonyms: Avicel PH, Celex, cellulose gel, Celphere, Ceolus KG, crystalline cellulose,
E460, Emcocel, Ethispheres, Fibrocel, Pharmacel, Tabulose, Vivapur.
Chemical Name: Cellulose
Empirical Formula and Molecular Weight: (C6H10O5)n ≈36 000 where n ≈ 220.

Page 27
Structural Formula:
Figure 2.2: Chemical structure of microcrystalline cellulose
Functional Category: Adsorbent, suspending agent, tablet and capsule diluents, tablet
disintegrant.
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 compression
processes
Description: Microcrystalline cellulose is purified, partially depolymerized cellulose that
occurs as a white, odorless, tasteless, crystalline powder composed of porous particles.
Typical Properties:
Angle of repose: 49° for Ceolus KG; 34.4° for Emcocel 90M.9
Density (true): 1.512–1.668 gm / cm3
Flowability: 1.41 g / s for Emcocel 90M.9
Particle size distribution: Typical mean particle size is 20–200 μm. Different grades may
have a different nominal mean particle size; Avicel PH- 102a 100-60
Solubility: Slightly soluble in 5 % w/v sodium hydroxide solution; practically insoluble
in water, dilute acids, and most organic solvents.
Calcium phosphate, dibasic dihydrate
Nonproprietary Names: BP: Calcium hydrogen phosphate, JP: Dibasic calcium
phosphate, PhEur: Calcii hydrogenophosphas dihydricus, USP: Dibasic calcium
phosphate

Page 28
Synonyms: Calcium hydrogen orthophosphate dehydrate, calcium monohydrogen
phosphate dehydrate, Di-Cafos; dicalcium orthophosphate, DI-TAB, E341, Emcompress,
phosphoric acid calcium salt (1:1) dihydrate; secondary calcium phosphate.
Chemical Name: Dibasic calcium phosphate dehydrate
Empirical Formula and Molecular Weight: CaHPO4·2H2O; 172.09
Structural Formula: CaHPO4·2H2O
Functional Category: Tablet and capsule diluent.
Applications in Pharmaceutical Formulation or Technology: Dibasic calcium
phosphate dihydrate is widely used in tablet formulations both as an excipient and as a
source of calcium and phosphorus in nutritional supplements.
Description: Dibasic calcium phosphate dihydrate is a white, odorless, tasteless powder
or crystalline solid. It occurs as monoclinic crystals.
Typical Properties:
Angle of repose: 28.3° for Emcompress.
Density (bulk): 0.915 gm / cm3
Density (tapped): 1.17 gm / cm3
Density (true): 2.389 gm / cm3
Particle size distribution: DI-TAB: average particle diameter 180 μm, Fine powder:
average particle diameter 9 μm
Solubility: Practically insoluble in ethanol, ether, and water; soluble in dilute acids.
Lactose, Anhydrous
Nonproprietary Names: BP: Anhydrous lactose, JP: Anhydrous lactose, PhEur:
Lactosum anhydricum, USPNF: Anhydrous lactose
Synonyms: Anhydrous Lactose NF 60M, Anhydrous Lactose NF Direct Tableting,
Lactopress Anhydrous, lactosum, lattioso, milk sugar, Pharmatose DCL 21, Pharmatose
DCL 22, saccharum lactis, Super-Tab Anhydrous.

Page 29
Chemical Name: O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranose
Empirical Formula and Molecular Weight: C12H22O11 and 342.30
Structural Formula: Anhydrous lactose as O-β-D-galactopyranosyl-(1→4)-β-
Dglucopyranose; or a mixture of O-β-D-galactopyranosyl-(1→4)-α-D-glucopyranose and
O-β- D-galactopyranosyl-(1→4)-β-D-glucopyranose (Figure 2.3).
Figure 2.3: Chemical structure of anhydrous lactose
Functional Category: Binding agent, directly compressible tableting excipients,
lyophilization aid, tablet and capsule filler.
Applications in Pharmaceutical Formulation or Technology: Anhydrous lactose is
widely used in direct compression tableting applications and as a tablet and capsule filler
and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low
moisture content.
Description: Lactose occurs as white to off-white crystalline particles or powder. Several
different brands of anhydrous lactose are commercially available which contain
anhydrous β-lactose and anhydrous α-lactose.
Typical Properties:
Angle of repose: 39° for Pharmatose DCL 21 and 38° for Super-Tab Anhydrous.

Page 30
for anhydrous β-lactose; 1.567 gm / cm3
for Super-Tab
Anhydrous.
for Pharmatose DCL 21; 0.67 gm / cm3
for Pharmatose
DCL 22; 0.65 gm / cm3
for Super-TabAnhydrous.
for Pharmatose DCL 21; 0.79 gm / cm3
for Pharmatose
DCL 22; 0.87 gm / cm3
for Super-TabAnhydrous.
Solubility: soluble in water; sparingly soluble in ethanol (95 %) and ether.
Sodium starch glycolate
Nonproprietary Names: BP: Sodium starch glycollate, PhEur: Carboxymethylamylum
natricum, USPNF: Sodium starch glycolate
Synonyms: Carboxymethyl starch, sodium salt, Explosol, Explotab, Glycolys, Primojel,
starch carboxymethyl ether, sodium salt, Tablo, Vivastar P.
Chemical Name: Sodium carboxymethyl starch
Empirical Formula and Molecular Weight: Sodium starch glycolate is the sodium salt
of a carboxymethyl ether of starch, containing 2.8–4.2 % sodium. The molecular weight
is typically 5 × 105–1 × 106.
Structural Formula:
Figure 2.4: Chemical structure of sodium starch glycolate

Page 31
Functional Category: Tablet and capsule disintegrant.
Applications in Pharmaceutical Formulation or Technology: Sodium starch glycolate
is widely used in oral pharmaceuticals as a disintegrant in capsule and tablet
formulations. It is commonly used in tablets prepared by either directcompression or wet-
granulation processes. The usual concentration employed in a formulation is between 2 %
and 8 %, with the optimum concentration about 4 %, although in many cases 2 % is
sufficient. Disintegration occurs by rapid uptake of water followed by rapid and
enormous swelling. Although the effectiveness of many disintegrants is affected by the
presence of hydrophobic excipients such as lubricants, the disintegrant efficiency of
sodium starch glycolate is unimpaired. Increasing the tablet compression pressure also
appears to have no effect on disintegration time.10 – 14 sodium starch glycolate has also
been investigated for use as a suspending vehicle.
Description: Sodium starch glycolate is a white to off-white, odorless, tasteless, free-
flowing powder. It consists of oval or spherical granules, 30 – 100 μm in diameter, with
some less-spherical granules ranging from 10 – 35 μm in diameter.
Typical Properties:
Particle size distribution: 100 % of particles less than 106 μm in size. Average particle
size is 35 – 55 μm for Explotab.
Solubility: Sparingly soluble in ethanol (95 %), practically insoluble in water. At a
concentration of 2 % w/v sodium starch glycolate disperses in cold water and settles in
the form of a highly hydrated layer.
Swelling capacity: In water, sodium starch glycolate swells to up to 300 times its
volume.
Viscosity (dynamic): ≤ 200 mPa s (200 cP) for a 4 % w/v aqueous dispersion. Viscosity
is 4.26 mPa s for a 2% w/v aqueous dispersion
Starch
Nonproprietary Names: BP: Potato starch, JP: Potato starch, PhEur: Solani amylum
(potato starch), USPNF: Potato starch

Page 32
Synonyms: Amido, amidon, amilo, amylum, Aytex P, C*PharmGel, Fluftex W, Instant
Pure-Cote, Melojel, Meritena, Paygel 55, Perfectamyl D6PH, Pure-Bind, Pure-Cote,
Pure-Dent, Pure- Gel, Pure-Set, Purity 21, Purity 826, Tablet White.
Chemical Name: Starch
Empirical Formula and Molecular Weight: (C6H10O5) n 50 000–160 000 where n =
300–1000. Starch consists of amylose and amylopectin, two polysaccharides based on α-
glucose.
Functional Category: Glidant, diluents, disintegrant, tablet binder.
Structural Formula:
Figure 2.5: Chemical structure of starch
Applications in Pharmaceutical Formulation or Technology: Starch is used as an
excipient primarily in oral solid-dosage formulations where it is utilized as a binder,
diluent, and disintegrant. As a diluent, starch is used for the preparation of standardized
triturates of colorants or potent drugs to facilitate subsequent mixing or blending
processes in manufacturing operations. Starch is also used in dry-filled capsule
formulations for volume adjustment of the fill matrix.1 In tablet formulations, freshly
prepared starch paste is used at a concentration of 5–25 % w/w in tablet granulations as a
binder.

Page 33
Description: Starch occurs as an odourless and tasteless, fine, white-colored powder
comprising very small spherical or ovoid granules whose size and shape are characteristic
for each botanical variety.
Typical Properties:
for corn starch.
for corn starch.
for corn starch.
Flowability: Corn starch is cohesive and has poor flow characteristics.
Gelatinization temperature: 72 °C for potato starch
Particle size distribution: Potato starch: 10–100 μm;
Solubility: Practically insoluble in cold ethanol (95 %) and in cold water. Starch swells
instantaneously in water by about 5–10 % at 37 °C.2, 22 polyvalent cations produce more
swelling than monovalent ions, but pH has little effect.
Swelling temperature: 64°C for potato starch
Talc
Nonproprietary Names: BP: Purified talc, JP: Talc, PhEur: Talcum, USP: Talc
Synonyms: Altalc, E553b, hydrous magnesium calcium silicate, hydrous magnesium
silicate, Luzenac Pharma; magnesium hydrogen metasilicate, Magsil Osmanthus, Magsil
Star, powdered talc, purified French chalk, Purtalc, soapstone, steatite, Superiore.
Chemical Name: Talc
Empirical Formula and Molecular Weight: Talc is a purified, hydrated, magnesium
silicate, approximating to the formula Mg6(Si2O5)4(OH)4. It may contain small, variable
amounts of aluminum silicate and iron.
Functional Category: Anticaking agent, glidant, diluents, lubricant.
Applications in Pharmaceutical Formulation or Technology: Talc was once widely
used in oral solid dosage formulations as a lubricant and diluents.

Page 34
Typical Properties:
Hardness: 1.0 – 1.5
Moisture content: Talc absorbs insignificant amounts of water at 25 °C and relative
humidities up to about 90 %.
Solubility: It is practically insoluble in dilute acids and alkalis, organic solvents, and
water
Magnesium stearate
Nonproprietary Names: BP: Magnesium stearate, JP: Magnesium stearate, PhEur:
Magnesii stearas, USPNF: Magnesium stearate
Synonyms: Magnesium octadecanoate, octadecanoic acid, magnesium salt, stearic acid,
magnesium salt.
Chemical Name: Octadecanoic acid magnesium salt
Empirical Formula and Molecular Weight: C36H70MgO4 and 591.34
Structural Formula: [CH3 (CH2)16COO]2 Mg
Functional Category: Tablet and capsule lubricant.
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.
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:

Page 35
Flowability: Poorly flowing, cohesive powder.
Solubility: Practically insoluble in ethanol, ethanol (95 %), ether and water; slightly
soluble in warm benzene and warm ethanol (95 %).
Guar Gum
Nonproprietary Names: BP: Guar galactomannan, PhEur: Guar galactomannanum,
USPNF: Guar gum
Synonyms: E412; Galactosol; guar flour; jaguar gum; Meyprogat; Meyprodor;
Meyprofin.
Chemical Name: Galactomannan polysaccharide
Empirical Formula and Molecular Weight: (C6H12O6) n ≈220 000
Structural Formula: Guar gum consists of linear chains of (1→4)-β-D-mannopyranosyl
units with α-Dgalactopyranosyl units attached by (1→6) linkages. The ratio of D-
galactose to D-mannose is between 1: 1.4 and 1: 2 (Figure 2.6).
Figure 2.6: Chemical structure of guar gum
Functional Category: Suspending agent, tablet binder, tablet disintegrant, viscosity-
increasing agent.
Description: Guar gum is obtained from the ground endosperms of Cyamopsis
tetragonolobus (L.) Taub. (Family: Leguminosae). It consists chiefly of a highmolecular-
weight hydrocolloidal polysaccharide, composed of galactan and mannan units combined
through glycoside linkages, which may be described chemically as a galactomannan.

Page 36
Typical Properties:
Density: 1.492 gm / cm3
Solubility: Practically insoluble in organic solvents. In cold or hot water, guar gum
disperses and swells almost immediately to form a highly viscous, thixotropic sol. The
optimum rate of hydration occurs at pH 7.5 to 9.0. Finely milled powders swell more
rapidly and are more difficult to disperse. Two to four hours in water at room temperature
are required to develop maximum viscosity.
Viscosity: 4.86 Pa s (4860 cP) for 1 % w/v dispersion at 25 ºC temperature.
Stability and Storage Conditions: Guar gum powder should be stored in a well-closed
container in a cool, dry place. Aqueous guar gum dispersions have a buffering action and
are stable at pH 4.0 to 10.5.
Xanthan Gum
Nonproprietary Names: BP: Xanthan gum, PhEur: Xanthani gummi, USPNF: Xanthan
gum
Synonyms: Corn sugar gum; E415; Keltrol; polysaccharide B-1459; Rhodigel; Vanzan
NF; Xantural.
Chemical Name: Xanthan gum
Empirical Formula and Molecular Weight: (C35H49O29)n Approximately 2 × 106
Xanthan gum is a high molecular weight polysaccharide gum. It contains D-glucose and
D-mannose as the dominant hexose units, along with D-glucuronic acid, and is prepared
as the sodium, potassium, or calcium salt.
Functional Category: Stabilizing agent; suspending agent; viscosity-increasing agent.
Description: Xanthan gum occurs as a cream- or white-colored, odorless, free-flowing,
fine powder.
Typical Properties:
Acidity / alkalinity: pH = 6.0 – 8.0 for a 1 % w/v aqueous solution.

Page 37
Particle size distribution: Various grades with different particle sizes are available; for
example, 100 % less than 180 μm in size for Keltrol CG; 100 % less than 75 μm in size
for Keltrol CGF; 100 % less than 250 μm, 95 % less than 177 μm in size for Rhodigel;
100 % less than 177 μm, 92 % less than 74 μm in size for Rhodigel 200.
Solubility: Practically insoluble in ethanol and ether; soluble in cold or warm water.
Viscosity: 1200 to 1600 mPa s (1200–1600 cP) for a 1 % w/v aqueous solution at 25 °C.
Stability and Storage Conditions: Xanthan gum is a stable material. Aqueous solutions
are stable over a wide pH range (pH 3– 12), although they demonstrate maximum
stability at pH 4 – 10 and temperatures of 10 – 60°C. Xanthan gum solutions of less than
1 % w/v concentration may be adversely affected by higher than ambienttemperatures.
Hypromellose
Nonproprietary Names: • BP: Hypromellose,
• JP: Hydroxypropylmethylcellulose, • PhEur: Hypromellosum, • USP: Hypromellose
Synonyms: Benecel MHPC; E464; hydroxypropyl methylcellulose; HPMC; Methocel;
methylcellulose propylene glycol ether; methyl hydroxypropylcellulose; Metolose;
Tylopur.
Chemical Name: Cellulose hydroxypropyl methyl ether
Empirical Formula and Molecular Weight: The PhEur 2005 describes hypromellose as
a partly O-methylated and O-(2-hydroxypropylated) cellulose. It is available in several
grades that vary in viscosity and extent of substitution. Grades may be distinguished by
appending a number indicative of the apparent viscosity, in mPa s, of a 2 % w/w aqueous
solution at 20 °C. Hypromellose defined in the USP 28 specifies the substitution type by
appending a four-digit number to the nonproprietary name: e.g., hypromellose 1828. The
first two digits refer to the approximate percentage content of the methoxy group
(OCH3). The second two digits refer to the approximate percentage content of the
hydroxypropoxy group (OCH2CH (OH) CH3), calculated on a dried basis. It contains
methoxy and hydroxypropoxy groups conforming to the limits for the types of
hypromellose. Molecular weight is approximately 10 000 – 1 500 000.

Page 38
Structural Formula:
Figure 2.7: Chemical structure of cellulose hydroxypropyl methyl ether
Where R is H, CH3, or CH3CH (OH) CH2 (Figure 2.7)
Description: Hypromellose is an odorless and tasteless, white or creamy-white fibrous or
granular powder.
Typical Properties:
Melting point: Browns at 190 – 200 °C; chars at 225 – 230 °C. Glass transition
temperature is 170 – 180 °C.
Moisture content: Hypromellose absorbs moisture from the atmosphere; the
amount of water absorbed depends upon the initial moisture content and the
temperature and relative humidity of the surrounding air.
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. Certain grades of hypromellose are soluble in
aqueous acetone solutions, mixtures of dichloromethane and propan-2-ol, and
other organic solvents 6, 15, 35
.

Page 39
2.3. Literature review
Rahamathulla et al., 2019 was develop valsartan floating tablets (VFT) via non-
effervescent technique using low density polypropylene foam powder, carbopol, and
xanthan gum by direct compression. Before compression, the particulate powdered
mixture was evaluated for pre-compression parameters. The prepared valsartan tablets
were evaluated for post-compression parameters, swelling index, floating lag time, in
vitro buoyancy studies, and in vitro and in vivo X-ray imaging studies in albino rabbits.
The result of all formulations for pre- and post-compression parameters were within the
limits of USP. FTIR and DSC studies revealed no interaction between the drug and
polymers used. The prepared floating tablets had good swelling and floating capabilities
for more than 12 h with zero floating lag time. The release of valsartan from optimized
formulation NF-2 showed sustained release up to 12 h; which was found to be non-
Fickian release. Moreover, the X-ray imaging of optimized formulation (NF-2) revealed
that tablet was constantly floating in the stomach region of the rabbit, thereby indicating
improved gastric retention time for more than 12 h. Consequently, all the findings and
outcomes have showed that developed valsartan matrix tablets could be effectively used
for floating drug delivery system 36
.
Jain 2018, developed a simple Gastroretentive Mucoadhesive tablets of Riboflavin.
Mucoadhesion is one of the approach to prolong gastric retention. In these systems,
Mucoadhesion is achieved by using Mucoadhesive polymers which adhere to the
epithelial surface of gastrointestinal tract. Narrow absorption window mainly from
upper part of GIT and short half -life makes riboflavin an ideal candidate for its
formulation as a Mucoadhesive tablets. Hence we intend to develop a simple
Gastroretentive Mucoadhesive tablets of Riboflavin and prepare sustained release
once daily 37
.
Wagh et al., 2018 Gastroretentive drug delivery system (GRDDS) is one of the novel
approaches in the area of oral sustained release dosage forms. Gastro retentive dosage
forms has received significant interest in the past few decades as they can improve
the limitation of conventional and oral controlled release drug delivery system
related to fast gastric emptying time. Drugs that are easily absorbed from

Page 40
gastrointestinal tract (GIT) and have short half - lives are eliminated quickly
from the systemic circulation require frequent dosing to achieve suitable therapeutic
activity. To avoid these limitations, the development of oral sustain release GRDDS
is an attempt to release the drug slowly into the GIT and maintain an effective drug
concentration in the systemic circulation for a long time. After oral administration,
such a drug delivery would be retained in the stomach and release the drug in controlled
manner so, that the drug could be supplied continuously to its absorption sited in
the GIT 38
.
More et al., 2018 compiled the various gastroretentive approaches. In order to
understand various physiological difficulties to achieve gastric retention, we have
summarized important factors controlling gastric retention. Oral route of drug
administration is the most preferable route because of its flexibility in formulation, ease
of administration, and patient compliance. But this route has certain limitations like
limited gastric residence time (GRT) for sustained drug delivery system and for the drugs
which are absorb from specific region of gastrointestinal tract (GIT). To overcome these
limitations, various approaches have been proposed to increase the gastric retention time
of the delivery system in the upper part of gastrointestinal tract. Gastroretentive dosage
form (GRDF) prolongs the GRT by targeting site-specific drug release in upper part of
GIT. GRDFs enable continuous and the extended duration of drug release and improve
bioavailability of drugs that have narrow therapeutic window, by this way they prolong
dosing interval and increase compliance of the patient. The evaluation parameters of
gastroretentive drug delivery systems are covered. The present review addresses briefly
about the current status of various leading gastroretentive drug delivery technologies,
developed until now, i.e. high density (sinking), floating, bio- or mucoadhesive,
expandable, unfoldable, super porous hydrogel, magnetic systems etc. In addition,
important factors controlling gastroretention, advantages and finally, future potential are
discussed 39
.
El Nabarawi et al., 2017 developed a controlled-release floating matrix tablet and
floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their
floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the
optimum matrix tablet, raft system formula, and marketed Duspatalin® 200 mg retard as

Page 41
reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft
system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively,
and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10
(Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared
tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11
(Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation,
providing sustained release of 82.1% within 8 h. Compared with the marketed MbH
product, the Cmax of FT-10 was almost the same, while FRS-11 maximum concentration
was higher. The tmax was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and
FRS-11, respectively. In addition, the oral bioavailability experiment showed that the
relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of
FT-10 and FRS-11, respectively, compared to marketed product. These results
demonstrated that both controlled-released floating matrix tablet and raft system would
be promising gastroretentive delivery systems for prolonging drug action 40
.
Kumari et al, 2016 developed sustained release formulation of Verapamil Hydrochloride
to maintain constant therapeutic levels of the drug for over 12 hrs. Various grades of
HPMC polymers, Guar gum, and Xanthum gum were employed as polymers. Verapamil
Hydrochloride dose was fixed as 120 mg. Total weight of the tablet was considered as
400 mg. Polymers were used in the concentration of 60, 120 and 180 mg concentration.
All the formulations were passed various physicochemical evaluation parameters and
they were found to be within limits. Whereas from the dissolution studies it was evident
that the formulation (F6) showed better and desired drug release pattern i.e.,96.10 % in
12 hours containing Guar gum polymer in the concentration of 180mg. It followed zero
order release kinetics. For the optimized formulation alcohol effect has been studied by
using various concentrations of alcohol in dissolution medium. As the concentration of
alcohol increased the sustained action of polymer was decreased. Hence it was concluded
that alcohol has significant effect on drug release pattern 41
.
Dawang et al., 2015 developed a prolonged release gastro retentive (GT) formulation of
Verapamil hydrochloride. Drug was evaluated by UV and DSC. 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

Page 42
properties, swelling, floating, and drug release. The purpose of this research was to
formulate and evaluation of a floating tablet of Verapamil hydrochloride by using Gastro
retentive technology using 32 factorial design. Floating tablets were prepared by
incorporating HPMC K15M, sodium alginate, sodium bicarbonate and citric acid. A 32
Factorial design was applied systemically; the amount of HPMC K15M (X1) and sodium
alginate (X2) were selected as independent variables. The time required for 100% drug
release and floating lag time (FLT) were selected as dependent variables. It was found
that HPMC K4M, sodium alginate and their interaction had significant influence on the
% drug release and floating lag time of the delivery system 42
.
Bharat et al, 2014, optimized bilayer gastric floating drug delivery system of Verapamil
hydrochloride to study the effect of formulation variables especially, combination of
polymers on drug release showing prolonged gastric residence time and optimized by
using mathematical and statistical techniques. Three ratios of drug to total polymer
content and three ratios of HPMC K4M to CP934 were chosen for an optimal design. In
the preliminary trials the effect of sodium bicarbonate loading was studied on floating
properties and 12% concentration was found to be optimum for floating buoyancy.
Hardness of about 5 kg/cm2 was found to be optimum for floating buoyancy and to keep
two layers intact. Other physical parameters like weight variation, thickness and friability
were within pharmacopoeial limit. Percentage drug content in all BFT formulations was
found to be 98.47% - 99.96% which were within pharmacopoeial limit. Drug-polymer
ratio and the HPMC K4M-CP934 significantly affect the buoyancy and drug release. It
was concluded on the basis of buoyancy and in-vitro release kinetics that an optimized
formulation containing a ratio of Drug to polymer 1:1 and polymer to polymer 1:1 gave
the best in-vitro release of 99.42% in 12 hrs while for 3:1 and 1:3 in-vitro release was
91.05% and 93.71% respectively. A comparative study was done with the marketed
formulation of Verapamil hydrochloride (Calaptin – SR). FTIR studies show no evidence
of interaction between drug, polymers and other excipients. The In vitro data were fitted
to different kinetic models 43
.
Kondeti et al., 2014 Sustained release matrix tablets reduce the frequency of the dosing
and increase the effectiveness of the drug by localization at the site of action, providing
uniform drug delivery. Sustained release matrix tablets of verapamil hydrochloride were

Page 43
prepared by using HPMC K15M, Xanthan and Guar Gum polymers with different
concentration in various batches of the formulations to facilitate the drug release which
cause patient compliance as the dosing frequency is reduced. Verapamil HCl was
considered as an ideal drug for designing sustained release formulation because of the
high frequency of administration and short biological half-life. The sustained release
matrices of Verapamil HCl were prepared by wet granulation technique. Drug release
was studied by using Dissolution testing apparatus 2 (paddle method) with 0.1 N HCl for
2 hours followed by pH 6.8 Phosphate buffer for 8 hours. The in vitro drug release of
various formulations was performed and compared. The results shows that the tablets
formulated with HPMC K15M polymer shows more sustained action when compared to
that of Xanthan and Guar gum. The high viscosity of the polymers binds the formulation
of matrix thus sustains the release of drug. It was also observed that the increase in
concentration of the polymer decreased the drug release from the polymer matrix 44
.
Vidyadhara et al., 2014, developed osmotic controlled extended release formulations of
verapamil hydrochloride an angiotensin II receptor antagonist with anti‑hypertensive
activity. Verapamil hydrochloride matrix tablets were prepared by direct compression
process using hydroxypropyl methylcellulose (HPMC) K 15M as polymeric material and
mannitol as osmogen at varied concentrations. The matrix tablets were further coated
with different compositions of ethylcellulose7cps and polyethylene glycol (PEG)‑4000
by pan coating method. Physical parameters such as weight uniformity, drug content,
hardness and friability were evaluated for uncoated tablets and were found to be within I.
P limits. The coating thickness and percentage of coating applied for various tablets were
also evaluated. The optimized coated tablets were further subjected to micro drilling on
the upper face to get 0.5 µm orifice diameter. All the tablets were further subjected to
dissolution studies by using USP apparatus II with 6.8 pH phosphate buffer as medium.
These studies indicated that all the tablets were found to release the drug up to 12 hours,
while coated tablets with orifice found to release the drug at zero order rate, which was in
good agreement with peppas n > 0.9 45
.
Tola and Li 2014 developed a hydrophobic polymer to overcome the issue of pH-
dependent release of weakly basic model drug verapamil hydrochloride from matrix
tablets without the use of organic buffers in the matrix formulations. Providing pH-

Page 44
independent oral release of weakly basic drugs with conventional matrix tablets can be
challenging because of the pH-dependent solubility characteristics of the drugs and the
changing pH environment along the gastrointestinal tract. Silicone pressure-sensitive
adhesive (PSA) polymer was evaluated because of its unique properties of low surface
energy, hydrophobicity, low glass transition temperature, high electrical resistance, and
barrier to hydrogen ion diffusion. Drug release, hydrogen ion diffusion, tablet contact
angle, and internal tablet microenvironment pH with matrix tablets prepared using PSA
were compared with those using water-insoluble ethyl cellulose (EC). Silicone PSA films
showed higher resistance to hydrogen ion diffusion compared with EC films. Verapamil
hydrochloride tablets prepared using silicone PSA showed higher hydrophobicity and
lower water uptake than EC tablets. Silicone PSA tablets also showed pH-independent
release of verapamil and decreased in dimensions during drug dissolution. By contrast,
verapamil hydrochloride tablets prepared using EC did not achieve pH-independent
release 46
.
Syeda et al., 2013 formulated Gastro retentive controlled release drug delivery system of
Verapamil HCl to increase the gastric retention time of the dosage form with controlling
the drug release pattern. Different grades of hydroxy propyl methyl cellulose derivatives;
Methocel K4M and Methocel K15MCR were incorporated for their gel forming
properties. Tablet buoyancy was achieved by incorporating a mixture of gas generating
agents; sodium bicarbonate and anhydrous citric acid. In vitro dissolution studies were
carried out for eight hours using USP XXII paddle type apparatus using 0.1N HCl as the
dissolution medium. All the gastro retentive tablets showed good in vitro buoyancy.
Tablets swelled radially and axially during buoyancy study. The release kinetics were
explored and explained with zero order, first order, Higuchi and Korsmeyer equations.
The release rate, extent and mechanisms were found to be governed by polymer type and
content. Formulations were characterized by physical characterization, drug loading
content and Fourier Transform Infrared spectroscopy (FT-IR). Good results were
obtained in the tests and the FT-IR spectroscopic studies indicating no interaction and the
stability of Verapamil HCl in the used excipients. Based up on the results, it was proved
that a proper balance between rate retarding polymer and gas forming agents is obligatory
for efficient buoyancy and controlled drug release 47
.

Page 45
Sahi al., 2013, developed the Verapamil hydrochloride sustained-release floating matrix
tablets using gas-generation approach to prolong the gastric residence time. Floating
tablets were prepared using hydroxypropyl methylcellulose K4M (HPMC) as hydrophilic
gel material, sodium bicarbonate as gas-generating agent and Citric Acid as floating
assistant agent. A 32 factorial design was used to select the optimized formulation
wherein HPMC K4M (X1) and Citric Acid (X2) were taken as independent variables and
Floating lag time (FLT), amount of drug release after 24hrs. (Q24) were taken as
dependent variables. The release data were evaluated by the model-dependent (curve
fitting) method using PCP Disso v2.08 software. Optimisation studies were carried out by
using the Design Expert software (version 8.0.1). The floating tablets were evaluated for
uniformity of weight, hardness, thickness, swelling index, friability, drug content, FLT,
and in vitro release. The in vitro drug release followed Hixson-Crowell model and
mechanism of drug release was found to be anomalous or non-fickian type. The
optimized formulation was F3 containing HPMC K4M 15%, and Citric acid 3% having
minimum FLT and maximum drug release after 24 hrs 48
.
Ray and Gupta, 2013 formulated Matrix tablets of Verapamil Hydrochloride as
sustained release tablet employing sodium alginate, hydroxyl propyl methyl cellulose
polymer, Ethyl cellulose and the sustainedrelease tablets was investigated. Sustained
release matrix tablets contain 240 mg Verapamil Hydrochloride were developed using
different drug polymer concentration of HPMC, Sodium Alginate and Ethyl Cellulose.
Tablets were prepared by wet granulation using HPMCand water solution. Formulation
was optimized on the basis of acceptable tablet properties and in-vitro drug release. The
resulting formulation produced robust tablets with optimum hardness, thickness
consistent weight uniformity and low friability. All tablets but one exhibited gradual and
near completion sustained release for Verapamil Hydrochloride, and 99% to 101%
released at the end of 24 hrs. The results of dissolution studies indicated that formulation
F8, the most successful of the study. An increase in release kinetics of the drug was
observed on decreasing polymer concentration 49
.
Mathur et al., 2013 developed a sustained release matrix tablet of verapamil
hydrochloride (VH) using ethyl cellulose, methyl cellulose, Eudragit RS 100,
hydroxypropyl methylcellulose and carboxymethyl cellulose and to evaluate the drug

Page 46
release kinetics.Verapamil hydrochloride (VH) is a calcium channel blocking agent used
in the treatment of hypertension, cardiac arrhythmia and angina pectoris. The short
half‑life and high frequency of administration of VH makes it a suitable candidate for
designing sustained drug delivery system. In order to achieve the required sustained
release profile, the tablets were prepared by a wet granulation method using avicel PH
101 and magnesium stearate as binder and lubricant, respectively. The formulated tablets
were characterized for pre‑compression and post‑compression parameters and they were
in the acceptable limits. The drug release data obtained after an in vitro dissolution study
was fitted to various release kinetic models in order to evaluate the release mechanism
and kinetics. The criterion for selecting the best fit model was linearity (coefficient of
correlation). Drug release mechanism was found to follow a complex mixture of
diffusion, swelling and erosion. Furthermore, to minimize the initial burst drug release,
batches were coated by using Eudragit RS100 polymer. After coating the tablets, a better
release profile of the formulated tablets was expected and the release rate of the drug was
compared with the marketed SR tablet of VH 50
.
Vidyadhara et al., 2013 developed controlled release matrix tablets of verapamil
hydrochloride to increase therapeutic efficacy, reduced frequency of administration and
improved patient compliance. Verapamil hydrochloride was formulated as oral controlled
release matrix tablets by using the polyethylene oxides (Polyox WSR 303). They
investigate the influence of polymer level and type of fillers namely lactose (soluble
filler), swellable filler (starch 1500), microcrystalline cellulose and dibasic calcium
phosphate (insoluble fillers) on the release rate and mechanism of release for verapamil
hydrochloride from matrix tablets prepared by direct compression process. Higher
polymeric content in the matrix decreased the release rate of drug. On the other hand,
replacement of lactose with anhydrous dibasic calcium phosphate and microcrystalline
cellulose has significantly retarded the release rate of verapamil hydrochloride.
Biopharmaceutical evaluation of satisfactory formulations were also carried out on New
Zealand rabbits and parameters such as maximum plasma concentration, time to reach
peak plasma concentration, area under the plasma concentration time curve(0‑t) and area
under first moment curve(0‑t) were determined. In vivo pharmacokinetic study proves

Page 47
that the verapamil hydrochloride from matrix tablets showed prolonged release and were
be able to sustain the therapeutic effect up to 24 h 51
.
Patel et al., 2013 formulated novel gastro retentive controlled release drug delivery
system of verapamil HCl to increase the gastric retention time of the dosage form and to
control drug release. Hydroxypropylmethylcellulose (HPMC), carbopol, and xanthan
gum were incorporated for gel forming properties. Buoyancy was achieved by adding an
effervescent mixture of sodium bicarbonate and anhydrous citric acid. In vitro drug
release studies were performed, and drug release kinetics was evaluated using the linear
regression method. The optimized intragastric floating tablet composed of 3:2 of HPMC
K4M to xanthan gum exhibited 95.39% drug release in 24 h in vitro, while the buoyancy
lag time was 36.2 s, and the intragastric floating tablet remained buoyant for >24 h. Zero-
order and non-Fickian release transport was confirmed as the drug release mechanism
from the optimized formulation (F7). X-ray studies showed that total buoyancy time was
able to delay the gastric emptying of verapamil HCl intragastric floating tablet in mongrel
dogs for more than 4 h. Optimized intragastric floating tablet showed no significant
change in physical appearance, drug content, total buoyancy time, or in vitro dissolution
pattern after storage at 40°C/75% relative humidity for 3 months 52
.
Nikam et al., 2011 formulated A novel gastro retentive controlled release drug delivery
system of verapamil HCl to increase the gastric retention time of the dosage form and to
control drug release. Gastro retentive systems can remain in the gastric region for several
hours and hence significantly prolong the gastric residence time of drugs. Verapamil
HCL belongs to the class of calcium channel blockers. These medication block the
movement of the calcium into the muscle cells of the coronary arteries. They design and
evaluate verapamil HCL floating controlled release gastroretentive tablets using different
hydrocolloid polymers including Carbopol, Hydroxy propyl methyl cellulose, and
Xanthan gum incorporated for gel forming agent by direct compression technology. The
tablets were evaluated for the physicochemical parameters such as weight variation,
thickness, friability, hardness, drug content, in vitro buoyancy studies, in vitro dissolution
studies. The prepared tablets exhibited satisfactory physico-chemical characteristics.
Tablet buoyancy was achieved by adding an effervescent mixture of sodium bicarbonate
and anhydrous citric acid. The in vitro dissolution studies were carried out in a USP XXII

Page 48
apparatus II in 0.1N HCl. All the gastroretentive tablets showed good in-vitro buoyancy.
The selected tablets (F3) containing Xanthan gum released approximately 94.43% drug in
24 h in vitro dissolution study, while the buoyancy lag time was 25.8 ± 4.2 second and
the tablet remained buoyancy for > 24 h. Zero order and non-Fickian release transport
was confirmed as the drug release mechanism for the selected tablets (F3) 53
.
Gangadharappa et al., 2010 developed a controlled release floating drug delivery
system (tablet) of verapamil hydrochloride. Floating tablets of verapamil hydrochloride
were engineering to extend gastric residence time and hence to enhance its
bioavailability. The floating matrix tablets were prepared by direct compression
technique using a combination of hydroxyl propyl methyl cellulose (HPMC) and karaya
gum as polymers and sodium bicarbonate as generating agent. The prepared floating
tablets were evaluated for weight variation test, hardness, thickness, swelling index, in
vitro floating capabilities, floating lag time, compatibility studies, and in vitro drug
release. This swellable hydrophilic natural karaya gum was used to control the release of
drug. The results showed that the optimized formulation F8 containing 23.3% of karaya
gum (70 mg) and 13.3% of HPMC (40 mg) had good floating capability, shorter floating
lag time, and sustained drug release for the period of 8 h 54
.
Molke et al., 2010, prepared a gastroretentive drug delivery system of Verapamil HCL.
Floating tablets of Verapamil HCL were prepared employing solid dispersion technique
with compritol-888ATO. By using different release enhancer like Lactose,
Microcrystaline cellulose & HPMC K 100 LV. Cetyl alcohol was incorporated as a lower
density agent. The floating tablets were evaluated for uniformity of weight, hardness,
friability, drug content, in vitro buoyancy and dissolution studies. The effect of release
enhancer on drug release profile and floating properties was investigated. The prepared
tablets exhibited satisfactory physico-chemical characteristics. The drug release from the
tablets was sufficiently sustained and Fickian transport of the drug from tablets was
confirmed. The fabricated floating tablet formulations were subjected for stability study
at 400C and relative humidity at 75 % for three months. The product was evaluated for,
buoyancy, drug content and in vitro dissolution test. After stability study drug release
increased slightly but there is no change in physical appearance 55
.

Page 49
CHAPTER 3: PLAN OF WORK & HYPOTHESIS
3.1: OBJECTIVE:
The objective of the present investigation was to develop a formulation
gastroretentive nizatidine mucoadhesive microballons for treatment of peptic ulcer
mainly at gastric part of GIT, to improve gastric residence time and increase
bioavailability.
: HYPOTHESIS:
A major problem for gastric delivery is the attainment of an optimal concentration
at site of action with maximum bioavailability of drugs. The problem is associated with
the conventional dosage form for peptic ulcer diseases is frequent dosing due to the low
half life. The bioavailability of an instilled compound is generally low from 1.5 – 3.0 h
and low solubility, with only a small fraction reaching the target site.
In the present study an attempt was made to develop a mucoadhesive
Microballons of Nizatidine with variation in polysaccharide polymeric combination with
different ratios to increase mucoadhesion at gastric mucosa, which increase the gastric
residence time, thus increase the bioavailability.
: PLAN OF PRESENT WORK: The study included the following.
: Preformulation Study:
i. Exhaustive literature survey: The exhaustive literature survey about drugs and
various polymers used in present study was done.
ii. Analytical methods: The drug samples (Nizatidine) was studied for determination of
absorption maxima (λmax) in solvents i.e. gastric pH 0.1 N HCl. The analytical method
was validated in terms of preparation of calibration curve, specificity, repeatability
precision, intermediate precision and accuracy.
iii. Preformulation studies of drug sample: The drug samples were studied for
organoleptic properties, microscopic examination by using phase contrast microscope.
The physical characteristics of drug samples i.e. density, particle size, flow properties,

Page 50
compatibility, solubility in various dissolution medias, partition coefficient and drug-
excipients compatibility study were characterized.
: Formulation and characterization of mucoadhesive Microballons: These prepared
systems were evaluated with various parameters such as the physical properties i.e., Flow
properties determination, particle size measurement, shape and surface morphology,
mucoadhesive properties, swelling study, percentage yield, drug entrapment efficiency,
in-vitro drug release studies and Stability Studies etc.
: Result and discussion: This section was included all the results of present research
work.
: Summary and conclusion: This section was included summary and conclusion of
present research work.

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