14CD1S0906

DESIGN AND FORMULATION OF CONTROLLED POROSITY
OSMOTIC PUMP BASED DRUG RELEASE OF GLIPIZIDE
Thesis Submitted to
Jawaharlal Nehru Technological University, Kakinada
in partial fulfillment of the requirement for the award of the degree of
MASTER OF PHARMACY
in
INDUSTRIAL PHARMACY
By
KATTAMURI THULASI BHAVANI
B.Pharm
[Reg. No. 14CD1S0906]
Under the guidance of

INSTITUTIONAL GUIDE: INDUSTRIAL GUIDE:
Mr. Raghavendra Kumar Gunda,
M.Pharm
K.Rama Babu M.Pharm
Asst. professor Active Pharma labs
NIPS Hyderabad.
Department of Industrial Pharmacy

NARASARAOPETA INSTITUTE OF PHARMACEUTICAL SCIENCES
Kotappakonda Road, Yallamanda (P), Narasaraopet (M)
Guntur (Dt.) Pin: 522601
2015-2016
NARASARAOPETA INSTITUTE OF PHARMACEUTICAL SCIENCES:
NARASARAOPET
DECLARATION BY THE CANDIDATE
I KATTAMURI THULASI BHAVANI, of II year M. Pharmacy bearing Regd. No
14CD1S0906 hereby declare that the Research work entitled DESIGN AND
FORMULATION OF CONTROLLED POROSITY OSMOTIC PUMP BASED
DRUG RELEASE OF GLIPIZIDE was carried out by me under the guidance of
Mr. Raghavendra Kumar Gunda (College Guide) Mr. K.Rambabu (Industrial
Guide). The work embodied in this thesis is original and has not been submitted in part
or in full for any degree or diploma of this or other university.
Place:
Date: Name and Signature of the Student

ACKNOWLEDGEMENTS
This thesis is the end of my journey in obtaining my Master of Pharmacy. This thesis
has been kept on track and been seen through to completion with the support and
encouragement of numerous people including my well wishers, my friends, and
various institutions. At the end of my thesis, it is a pleasant task to express my thanks
to all those who contributed in many ways to the success of this study and made it an
unforgettable experience for me.
At this moment of accomplishment, I am extremely indebted to my guide Mr.

Raghavendra Kumar Gunda, M.pharm Asst. professor, Department of
Pharmaceutics. This work would not have been possible without his guidance,
support and encouragement. Under his guidance. I successfully overcame many
difficulties and learned a lot. It has been an honor to be his student and I thank him for
spending all his contributions of time and ideas to make my project experience
productive and stimulating.
My Sincere thanks to our college principal, Dr. J.N.Suresh Kumar, M.Pharm, Ph.D.
for his extreme support throughout my journey. Without his support this project work
could not be possible.
My Sincere thanks to Dr. Chandan Kumar Brahma M.pharm., Ph.D Department

of Pharmaceutics Mr. M.V. Anjaneyulu, M.Pharm Department of Pharmaceutics,
Mrs. A.V.S.Madhulatha, M.Pharm Department of Pharmaceutics. Mrs. T. Swaroopa
Rani, M.Pharm. Department of Pharmacology, Narasaraopeta Institute of
Pharmaceutical Sciences, Narasaraopeta. For extending their support towards the
success of this project.
I am also very much thankful to Mr. K. Nagaraju, Librarian of Narasaraopeta

Institute of Pharmaceutical Sciences, Narasaraopeta. Who helped to utilize the library
facilities of our college.
I am thankful to all the Teaching Staff of Narasaraopeta Institute of
Pharmaceutical Sciences, for their timely help and support.
I would like to pay high regards to My Parents and My Brother for their
sincerely encouragement and inspiration throughout my research work and lifiting me
uphill this phase on life. I owe everything to them.
KATTAMURI THULASI BHAVANI

CONTENTS
S.NO CHAPTER PAGE NO.
1. INTRODUCTION 01-17
2. AIM& OBJECTIVE 18-19
3. PLAN OF WORK 20
4. LITERATURE SURVEY 21-24
5. MATERIALS AND METHODS 25-47
6. RESULTS AND DISCUSSION 48-61
7. SUMMARY AND CONCLUSION 62-63
8. REFERENCES 64-67
LIST OF FIGURES
S.No Title Page No.

1 Plasma drug concentration profiles 4
2 Working principle of osmosis 6

3 Three chamber rose nelson pump 9
4 Drug release mechanism of osmotic pump tablets 11

5 Chemical structure of Glipizide 26
6 Chemical structure of PEG 31
7 Coating machine 39
8 Calibration curve of glipizide 49
9 FTIR of glipizide pure drug 49
10 FTIR of polyox WSRcoagulant 50
11 Comparative grafh of all 53
12 Zero order release 55
13 First order release 55
14 Higuchi model 56
15 Kores peppas model 56
LIST OF TABLES
S.NO TITLE PAGE NO

1 Advantages of controlled release formulations 1
2 Osmotic pressures of osmogens 7
3 Single chamber osmotic pumps 10
4 Multi chamber osmotic pumps 10
5 List of materials used in experiment 25
6 Pharmacokinetic parameters of glipizide 28
7 Uses of Nacl 32
8 List of equipments 34
9 FTIR spectra of pure drug 35
10 Formulation table of Glipizide 37
11 Coating composition of tablets 38
12 Coating machine (NEO COTA) process parameters and its limits 39
13 Coating machine (NEO COTA) process parameters and its limits 40
14 USP limits for flow properties 42
15 Pharmacoepial specification of tablet weight variation 43
16 Release mechanism Korsmeyer Peppas kinetic model 47
17 Organoleptic properties of glipizide 48
18 Calibration curve of glipizide 48
19 Flow properties of glipizide 50
20 Precompressive parameters of Glipizide 51
21 Evaluation results of compressed tablets 52
22 Cumulative % of drug release 53
23 Drug release kinetic model 21
24 Drug conent data of stability 61
25 In vitro drug release data of the stability formulation 61
ABBREVIATIONS
FT IR Fourier Transformer Infrared Spectroscopy
Hcl Hydrochloric acid
HPMC Hydroxy propyl methyl cellulose
GIT Gastrointestinal tract
ER Extended Release
SR Sustained Release
CR Controlled Release
CRDDS Controlled Release Drug Delivery System
BCS Biopharmaceutical Classification System
AUC Area Under the Curve
IP Indian Pharmacopoeia
BP British Pharmacopoeia
Ph Eur European Pharmacopoeia
USP United States Pharmacopoeia
PVP Polyvinyl pyrolidone
IPA Isopropyl alcohol
UV Ultraviolet Spectroscopy
BD Bulk Density
TD Tapped Density
INTRODUCTION
INTRODUCTION
The oral route for drug delivery is the most popular, desirable, and most preferred method for
administrating therapeutically agents for systemic effects because it is a natural, convenient, and cost
effective to manufacturing process. Oral route is the most commonly used route for drug administration.
Although different routes of administration are used for the delivery of drugs, oral route remains the
preferred mode. Even for sustained release systems the oral route of administration has been investigated
the most because of flexibility in designing dosage forms. From many decades, conventional dosage
forms, which are of prompt releasing nature, are used for treatment of acute and chronic diseases. The
conventional dosage forms provide no control over release of drug. To maintain the drug concentration
within the therapeutically effective range, it is often necessary to take these types of conventional dosage
forms several times a day. This results in significant fluctuations in drug levels1. Recently, several
technical advancements have been made. These have resulted in the development of new techniques in
drug delivery. These techniques are capable of controlling the rate of drug delivery, sustaining the
duration of therapeutic activity and/or targeting the delivery of drug to a tissue. The role of drug delivery
today is to take a therapeutically effective molecule with suboptimal physicochemical and/or
physiological properties and develop an optimized product that will still be therapeutically effective but
with added benefits. This is accomplished using the concepts of bioavailability enhancement and
controlled release. Incorporating an existing drug into a new drug delivery system can significantly
improve its performance in terms of efficacy, safety, and improved patient compliance2,3.
Table No: 1 Advantages of controlled release dosage forms over conventional forms.
Advantage Explanation
Reduction in drug blood By controlling the rate of drug release, peaks and
level fluctuation valleys of drug blood levels are eliminated
Frequency reduction in dosing Extended release products deliver frequently more

than a single dose of medication and thus they may
be taken less often than conventional forms
DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 1

INTRODUCTION
Enhanced patients With less frequency of dose administration, a

convenience and compliance patient is less apart to neglect taking a dose. There
is also greater patient and/or caregiver convenience
with dynamic and nighttime medication
administration
Reduction in adverse side Because there are fewer drug blood level peaks
effects outside of the drugs therapeutic range and into the
toxic range, adverse side effects occur less
frequently.
Reduction in overall health Although the initial cost of extended-release

care costs dosage forms may be greater than that for
conventional dosage forms, the overall cost of
treatment may be less due to enhanced therapeutic
benefit, fewer side effects, and reduced time
required of health care personnel to dispense and
administer drugs and monitor patients.
It is advantageous to deliver some drugs with short half- life and which are to be given frequently for chronic
ailments, in the form of controlled release formulations. The majority of existing oral controlled release systems
are matrix based, and their principle drug release mechanism is based on drug diffusion through the matrix
system. The diffusion is altered by the pH of the medium, the presence of food, hydrodynamic conditions, and
the bodys other physiological factors, all of which can cause difficulty in controlling the drug release rate and
result in poor in vivo - in vitro correlations (IVIVC) 4. Another delivery method used is the osmotic drug
delivery system, which utilizes the principle of osmotic pressure for the controlled delivery of active agent. The
release rate of drug from these systems is independent of the physiological factors of the gastrointestinal tract to
a large extent. Osmotic systems have a high degree of IVIVC, because of the factors that are responsible for
causing differences in release profiles in in vivo and in vitro (e.g variable pH, agitation) affect the systems to a
much lesser extent5,6.

INTRODUCTION
Out of existing oral controlled release systems, elementary osmotic pump, push pull osmotic pump, and
controlled porosity osmotic pump are the key systems. The controlled-porosity osmotic pump tablet is a spray-
coated or coated tablet with semi permeable membrane (SPM) containing leach able pore forming agents. They
do not have any aperture to release the drugs; drug release is achieved through the pores, which are formed in
the semipermeable wall in situ during the operation. In this system, the drug, after dissolution inside the core, is
released from the osmotic pump tablet by hydrostatic pressure and diffusion through pore screened by the
dissolution of pore formers incorporated in the membrane. The hydrostatic pressure is created either by an
osmotic agent or by the drug itself or by a tablet component, after water is imbibed across the semipermeable
membrane. The release rate from these types of systems is dependent on the coating thickness, level of leach
able components in the coating, solubility of the drug in the tablet core, and osmotic pressure difference across
the membrane but is independent of the pH and agitation of the release media7.
1.1 SOLID ORAL DOSAGE FORMS
Drugs can be administered through different routes, however of all the routes of administration, oral route of
administration is most convenient for administratingdrugs for systemic effect because of ease of administration
by manufacturing and dosage administration8.
Oral route of drug administration has wide acceptable and of the drugs administered orally in solid dosage forms
represents the preferred class of products. Solid dosage forms of tablets and capsules are more commonly
employed, the tablets have advantage than capsules in that they are tamper resistant and any adulterate of tablets
after its manufacture is about certain to be observed9.
Based on the duration of drug release solid orals are classified as
Conventional release (Immediate release)
Modified release dosage forms
Different terminology used in modified release dosage forms:
1. Extended Release Dosage Forms:
A dosage form that allows at least a two fold reduction in dose frequency as compared to the drug presented as
an immediate release10.
Example: controlled release, sustained release.
a. Sustained Release: It includes any drug delivery system that achieves slow release of drugs over an extended
of time not particularly at pre-determined rate.
b. Controlled Release: It includes any drug delivery system from which the drug is delivered at a
predetermined rate over long period.

INTRODUCTION
2. Delayed Release Dosage Forms:

A dosage form releases a discrete portion of drug at a time or times other than promptly after administration
although one portion may be released promptly after administration.
Example: enteric coated dosage forms.
3. Targeted Release Dosage Forms:
A dosage forms that release drug at/ near the intended physiological site of action. Targeted release dosage
forms may have extended release characters.
4. Repeat Action Dosage Forms:
It is a type of modified release drug product that is designed to release one dose or drug initially followed by
followed by a second dose of drug at a later time11.
Fig.1 Plasma drug concentration profiles for conventional tablet or capsule formulation (---) and a zero
order controlled release formulation ( ---).
MEC = Minimum Effective Concentration; MSC = Maximum Safe Concentration
5. Prolonged action dosage forms:
It is designed to release the drug slowly and to provide a continuous supply of drug over an extended period.
Extended release dosage forms are formulated in such a manner as to make the contained drug available over an
extended period of time following administration. Expressions such as controlled release, prolonged action,
repeat action, and sustained action have been used to describe such dosage forms. A typical controlled release
systems is designed to provide constant or nearly constant drug levels in plasma with, reduced fluctuations via
slow release over an extended period of time. More common methods that are used to achieve modified release
of orally administered drugs are as follows12.

INTRODUCTION
a. Dissolution controlled release system

i) Encapsulation dissolution control
ii) Matrix dissolution control
b. Diffusion controlled release
i) Reservoir devices
ii) Matrix devices

c. Diffusion and dissolution controlled systems
d. Ion exchange resins
e. pH independent formulations
f. Altered density formulations
g. Osmotic ally controlled release
1.2 OSMOTIC DRUG DELIVERY SYSTEM (ODDS):
Osmotic devices are most promising strategy based system for controlled drug delivery. They are among the
most reliable controlled drug delivery system and could be employed as oral drug delivery systems or
implantable device. Osmosis is an aristocratic biophenomenon, which is exploited for development of delivery
systems with every desirable property of an ideal controlled drug delivery system. Osmotic system utilize the
principles of osmotic pressure for delivery of drug13.
Principle of Osmosis: Osmosis is defined as a process in which the solvent molecules pass through a
semipermeable membrane from a pure solvent to a solution or from a dilute solution to a concentrated solution. .
Abe Nollet first reported osmotic effect, but Pfeiffer pioneered the field by quantitating the osmotic effect. He
measured the effect by utilizing a membrane, which was selectively permeable to water but impermeable to
sugar 14 .
This membrane separated sugar solution from pure water. Pfeiffer observed a flow of water in to the sugar
solution that was halted when a pressure () was applied to the sugar solution, hence postulated that this
pressure, the osmotic pressure () of the sugar solution was directly proportional to the solution concentration
and absolute temperature. Vans Hoff established the analogy between the Pfeffer results and the ideal gas laws
by the expression
V = nRT (1)
Where, is the osmotic pressure in atm, V is the volume of solutions in liters, n is the number of moles of
solutes, R is gas constant equal to 0.082 liter atm/mole and T is the absolute temperature

INTRODUCTION
Fig.2 Working principle of osmosis

The Vans Hoff equation presents a good means for calculating the osmotic pressures of solutes across perfect
semipermeable membranes and is accurate for low solute concentrations. But if the membrane is not completely
semipermeable and permits passage for solute along with solvent, the osmotic pressure calculated by above
equation will be more, when compared with experimental value. Concentrated solutions also show deviations
from these ideal equations another method of obtaining a good approximation of osmotic pressure is by utilizing
vapor pressure measurements and by using the expression
=RT/V In (P0/P) (2)
Where,
P0 is the vapour pressure of pure solvent,
P is the vapour pressure of the solution,
V is the molar volume of the solvent
Osmotic pressure for concentrated solutions of soluble solutes commonly used in controlled release
formulations are extremely high, ranging from 30 atm for sodium phosphate, up to 500 atm, for a lactose-
fructose mixture as shown in Table 2 These osmotic pressures can produce high water flows across
semipermiable membranes the osmotic water flow across the membrane is given by
dv/dt = A/l (3)
Where, dv/dt is the water flow across the membrane area A and thickness l, whose permeability is the osmotic
pressure difference between the two solutions on either side of the membrane.
This equation is strictly true for completely permeably selective membranes; that is membranes permeable to
water, but completely impermeable to the osmotic agent However this is a good approximation for most
membranes.

INTRODUCTION
Table No: 2 Osmotic pressures of saturated solutions of commonly used

Pharmaceutical solutes:
Inorganic water soluble osmogens Osmotic Pressure (Atm)
Sodium chloride 356
Potassium chloride 245
Potassium sulphate 39
Sodium phosphate tribasic 36
Sodium phosphate dibasic 31
Sodium phosphate monobasic 28
Organic osmogens
Fructose 355
Sucrose 150
Dextrose 82
Mannitol 138
Lactose-fructose 500
Dextrose-fructose 450
Sucrose-fructose 430
Mannitol-fructose 225
lactose-sucrose 250
Lactose-dextrose 225
Mannitol-sucrose 170
Osmosis is the phenomenon that makes controlled drug delivery a reality. Osmotic pressure created due to
imbibitions of fluid from external environment regulates the delivery of drug from the osmotic device. There are
various factors that govern a particular pattern of drug delivery like nature of semipermiable membrane,
diameter of delivery orifice, surface area of semipermeable. Membrane, pH, and electrolyte concentration in
external fluid, nature and concentration of osmogen etc15.
Advantages of ODDS:
Osmotic drug delivery systems for oral and parenteral use offer distinct and practical advantages over other
means of delivery. The following advantages have contributed to the popularity of osmotic drug delivery
systems
The delivery rate of zero- order (which is most desirable) is achieved with osmotic systems. Both in
vitro and in vivo experiments have established this fact.
Delivery may be delayed of pulsed, if desired.

INTRODUCTION
For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic conditions.
Higher release rates are possible with osmotic systems compared with conventional diffusion controlled
released drug delivery systems
The release rate of osmotic systems is highly predictable and can bepreprogrammed by modulating the
release control parameter.
A high degree of IVIVC is obtained in osmotic system.
The release from osmotic systems is minimally affected by the presence of food in the gastrointestinal
tract (GIT)16.
These advantages are attributed to the design of osmotic systems Environmental contents (e.g. GIT
fluids) do not gain access to the drug until the drug has been delivered out of the device.
. Osmotic systems have high degree of IVIVC, because the factors that are responsible for causing
differences in release profiles in invivo and in vitro (e.g. variable pH, agitation) affect these systems to
a much lesser extent17.
Classification of osmotic drug delivery system:
Many forms of osmotic pumps are reported in the literature but, in general they can be divided in oral and
implantable systems18. Osmotic Drug Delivery Devices fall in two categories
I. Implantable:
(a) The Rose and Nelson Pump.

(b) Higuchi Leeper Pump.
(c) Higuchi Theuwes pump.
(d) Implantable Miniosmotic pump.
II. Oral osmotic Pump
Single chamber osmotic pump:
Elementary osmotic pump, (EOP)
Multi chamber osmotic pump:
Push pull osmotic pump ( Tablets with a second expected osmotic chamber)
Osmotic pump with non expanding second chamber
Specific types:
Controlled porosity osmotic pump,
Osmotic bursting osmotic pump,
Liquid-oral osmotic pump(L-OROS),
INTRODUCTION
Delayed Delivery Osmotic device,

Telescopic capsule,
Colon targeted oral osmotic system(OROS-CT)
Sandwiched oral therapeutic system,
Osmotic pump for insoluble drugs,
Monolithic osmotic system
(a) Rose and Nelson Pump: The Osmotic pump was having three chambers. Water to be loaded prior to use
was the drawbacks of rose nelson osmotic pump19.
Fig.3 Three chamber rose nelson pump

(b) Higuchi-Leeper osmotic pump: The benefit of this pump over Rose Nelsonn pump is that it does not have
water chamber and the device is activated by water imbibed from the surrounding environment. This means the
pump is first prepared and then loaded with the drug and then store for weeks or months prior to use. Higuchi
and Leeper have proposed a number of variations of the Rose-Nelson pump and these designs have been
described in US patents20

INTRODUCTION
Table No: 3. Single Chamber Osmotic Pumps
Osmotic Design of Mechanism Application Figure

System dosage form
Elementa y Core: API + The water penetrates Moderately
Osmotic osmogen Inside the dosage form. soluble
Pump (EOP) Coat: Semi This results in formation API 60 -
permeable of saturated solution of 80%
Membrane with drug within the core. constant
delivery orifice release
Controlled Core: API + Delivery orifice is Poorly
-porosity osmogents formed by the soluble
osmotic Coat: Semi incorporation of a Drugs
pump permeable Leachable component.
(CPOP) membrane Once the tablet comes
containing water in contact with aqueous
soluble additives environment,
Watersoluble additives
dissolve lead to the
formation of a
microporous
membrane.
Table No: 4. Multi Chamber Osmotic Pumps

Osmotic Design of Mechanism Of Application Figure
system dosage form Drug release
From the
formulation
Push pull Core tablet: 2 After coming in This method is

osmotic layers contact with the suitable for
pumps Layer 1: API aqueous Poorly soluble
(ppop) +Polymer environment, in & highly
(complex) drug layer side drug Water soluble
osmogen polymer suspension drugs. For
Layer 2: will form, in push delivery of
Polymer + layer side polymer APIs Having
Osmogen+ going to swell and extremes of
colorant. push the drug layer Water
Coat: semi- to outside through solubility
permeable orifice. Modifications
membrane with can be done.
delivery orifice

INTRODUCTION
Sandwiched Core tablet: 3 The middle push API release

Osmotic layers layer swells from two sides
tablets Middle layer: and drug is released of tablet.
(SOTS) push layer 2 from delivery
Attached orifices present on
layers: API two sides of the
Coat: Semi tablet
permeable
membrane with
two side
delivery orifice.
(c) Higuchi- Theeuwes pump: In the early 1973 Higuchi Theeuwes developed a similar form of Rose Nelson
pump as shown the figure. The semi permeable wall itself acts as a rigid outer casing of the pump. The device is
loaded with drug prior to use. When the device is put in an aqueous environment the release of the drug follows
a time course set by the salt used in the salt chamber and the permeability of the outer membrane casing 21.
Basic component of controlled porosity osmotic pump
1. Drug:
Basic criteria for selection of drug
i. It should have short biological half-life and which is used for prolonged treatment are ideal candidate for
osmotic systems.
ii. It should be water soluble.
iii. It should be potent.
Fig. 4 Drug release mechanism of controlled porosity osmotic pump.

INTRODUCTION
2 Osmotic agent:
Osmogens are essential ingredient of the osmotic formulations. Upon penetration of biological fluid into the
osmotic pump through semipermeable membrane, osmogensare dissolved in the biological fluid, which creates
osmotic pressure buildup inside the pump and pushes medicament outside the pump through delivery orifice.
They include inorganic salts and carbohydrates. Mostly, potassium chloride, sodium chloride, and mannitol used
as osmogens. Generally combinations of osmogens are used to achieve optimum osmotic pressure inside the
system Eg: Water-soluble salts of inorganic acids: Magnesium chloride or sulfate; lithium, sodium, or potassium
chloride; lithium, sodium, or potassium sulfate; sodium or potassium hydrogen phosphate, etc
Eg: Water soluble salts of organic acids : Sodium and potassium acetate, magnesium succinate, sodium
benzoate, sodium citrate, sodium ascorbate, etc.
Eg: Carbohydrates: Arabinose, ribose, xylose, glucose, fructose, galactose, mannose, sucrose, maltose, lactose,
raffinose, etc.Water soluble amino acids: Glycine, leucine, alanine, methionine, etc. Organic polymeric
osmogents Sodium carboxy nmethylcellulose, HPMC, hydroxyethyl methylcellulose, cross-linked PVP,
polyethylene oxide, carbopols,polyacrylamides, etc.
3 Hydrophilic and Hydrophobic Polymers:
These polymers are used in the formulation development of osmotic systems for nmmaking drug containing
matrix core. The highly water soluble compounds can be coentrapped in hydrophobic matrices and moderately
water soluble compounds can be coentrapped in hydrophilic matrices to obtain more controlled release.
Generally, mixtures of both hydrophilic and hydrophobic polymers have been used in the development of
osmotic pumps of water-soluble drugs . The selection is based on the solubility of the drug as well as the
amount and rate of drug to be released from the pump. Ionic hydrogels such as sodium carboxymethyl cellulose
are preferably used because of their osmogenic nature. More precise controlled release of drugs can be achieved
by incorporating these polymers into the formulations. Examples: hydroxy ethyl cellulose, carboxy
methylcellulose, hydroxy propyl methylcellulose, high-molecular-weight poly (vinyl pyrrolidone), and
hydrophobic polymers such as ethyl cellulose and wax materials can be used for this purpose.
4 Coating solvents:
Solvents suitable for making polymeric solution that is used for manufacturing the wall of the osmotic device
include inert inorganic and organic solvents that do not adversely harm the core and other materials. The typical
solvents include methylene chloride, acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethyl acetate,
cyclohexane, carbon tetrachloride, and water. The mixtures of solvents such as acetone-methanol (80 : 20),

INTRODUCTION
acetone-ethanol (80 : 20), acetone-water (90 : 10), methylene chloride-methanol (79 : 21), methylene chloride-
methanol-water (75 : 22 : 3) can be used.
5 Plasticizers:
In pharmaceutical coatings, plasticizers, or low molecular weight diluents are added to modify the physical
properties and improve film-forming characteristics of polymers. Plasticizers can change visco elastic behavior
of polymers significantly . Plasticizers can turn a hard and brittle polymer into a softer, more pliable material,
and possibly make it more resistant to mechanical stress. Plasticizers lower the temperature of the second order-
phase transition of the wall or the elastic modules of the wall and also increase the workability, flexibility, and
permeability of the coating solvents. Generally from 0.001 to 50 parts of a plasticizer or a mixture of plasticizers
are incorporated into 100 parts of costing materials. PEG-600, PEG-200, triacetin (TA), dibutyl sebacate,
ethylene glycol monoacetate, ethylene glycol diacetate, triethyl phosphate, and diethyl tartrate used as
plasticizer in formulation of semipermeable membrane.
6. Semipermeable membrane:
Any polymer that is permeable to water but impermeable to solute can be used as a coating material in osmotic
devices Since the membrane in osmotic systems is semipermeable in nature, any polymer that is permeable to
water but impermeable to solute can be selected . Cellulose acetate is a commonly employed semipermeable
polymer for the preparation of osmotic pumps. It is available in different acetyl content grades. Particularly,
acetyl content of 32% and 38% is widely used. Acetyl content is described by the degree of substitution (DS),
that is, the average number of hydroxyl groups on the anhydro glucose unit of the polymer replaced by
substituting group e.g. Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate and
ethyl cellulose and Eudragits. Some other polymers such as agar acetate, amylose triacetate, betaglucan acetate,
poly (vinylmethyl) ether copolymers, poly (orthoesters), poly acetals, poly (glycolic acid) and poly (lactic acid)
derivatives.
Ideal properties of semipermeable membrane:
1. It should be stable to both outside and inside environments of the device.
2. It must be .sufficiently rigid so as to retain its dimensional integrity during the operational lifetime of the
device.
3. It should be relatively impermeable to the contents of dispenser so that osmogent is not lost by diffusion
across the membrane.
4. The membrane must be biocompatible.

INTRODUCTION
5. The material must possess sufficient wet strength (10-5 Psi) and wet modules so (10-5 Psi) as to retain its
dimensional integrity during the operational lifetime of the device.
6. The membrane must exhibit sufficient water permeability so as to attain water flux rates (dv/dt) in the desired
range. The water vapour transmission rates can be used to estimate water flux rates.
7. The reflection coefficient or leakiness of theosmotic agents should approach the limiting value of unity. But
polymer membranes must be more permeable to water.
7. Channeling agents or pore forming agents:
These are the water-soluble components which play an important role in the controlled drug delivery systems.
When the dissolution medium comes into contact with the semipermeable membrane it dissolves the channeling
agent and forms pores on the semipermeable barrier. Then the dissolution fluid enters the osmotic system and
releases the drug in a controlled manner over a long period of time by the process of osmosis.
Example of pore forming agent- sodium chloride, sodium bromide, potassium chloride, calcium chloride
calcium nitrate, glucose, fructosemannose, Diethylphthalate, Dibutylphthalate, Dibutylsebacate etc.
Factors affecting the release of drug through controlled porosity osmotic pump:
Drug: Osmotic agent ratio
As concentration of osmotic agent in the tablet core has increases the rate of drug release is also increases. It is
due to the increase in osmotic pressure on increasing the concentration of osmotic agent. As different osmotic
agent posses the different osmotic pressure the release of drug trough drug delivery system is depend on the
type of osmotic agent.
Level of coating thickness
Drug release from the system is inversely proportional to the level of coating thickness. As thickness of coating
increases the drug release decreases.
Porosity of coating membrane
As porosity of coating membrane get increases the rate of drug release is increases. The porosity of coating
membrane is depend on the type and concentration of channeling agent.
1.3 DIABETES MELLITUS:
Simply diabetes is a group of metabolic diseases in which a person has high blood sugar, either because the
pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced. This
high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst)
and polyphagia (increased hunger) 22.

INTRODUCTION
1 Types of diabetes mellitus (DM):

(a) Type 1 diabetes
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans
in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or
idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which beta cell loss is a T-cell-
mediated autoimmune attack. There is no known preventive measure against type 1 diabetes, which causes
approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise
healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal,
especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed
"juvenile diabetes" because a majority of these diabetes cases were in children.
"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to
describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-
dependent diabetes. This term, however, has no biologic basis and should not be used. There are many reasons
for type 1 diabetes to be accompanied by irregular and unpredictable hyperglycemia, frequently with ketosis,
and sometimes serious hypoglycemia, including an impaired counter regulatory response to hypoglycemia,
occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies
(e.g., Addison's disease).These phenomena are believed to occur no more frequently than in 1% to 2% of
persons with type 1 diabetes
(b) Type 2 diabetes
Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with relatively reduced
insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin
receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are
classified separately. Type 2 diabetes is the most common type. n the early stage of type 2, the predominant
abnormality is reduced insulin sensitivity. At this stage, hyperglycemia can be reversed by a variety of measures
and medications that improve insulin sensitivity or reduce glucose production by the liver.
Symptoms of Type 2 Diabetes:
Very often, people with type 2 diabetes will have no symptoms. When symptoms of type 2 diabetes happen,
they vary from person to person and include:
Increased thirst
Increased hunger (especially after eating)
Dry mouth

INTRODUCTION
Nausea and sometimes vomiting

Increased urination
Fatigue (weak, tired feeling)
Blurred vision
Numbness or tingling of the hands or feet
Frequent infections of the skin, urinary tract, or vagina
Sores that are slow to heal
Rarely, a person may be diagnosed with type 2 diabetes after falling into a diabetic coma.
(c) Other types of Diabeties:
i. Gestational diabetes:
Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of
relatively inadequate insulin secretion and responsiveness. It occurs in about 25% of all pregnancies and may
improve or disappear after delivery. Gestational diabetes is fully treatable, but requires careful medical
supervision throughout the pregnancy. About 2050% of affected women develop type 2 diabetes later in life.
Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to
the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and
skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause
respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction.
ii. Prediabetes:
Indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high
enough for a diagnosis of type 2 DM. Many people destined to develop type 2 DM spend many years in a state
of prediabetes which has been termed "America's largest healthcare epidemic.
iii. Latent autoimmune diabetes of adults (LADA):
It is a condition in which type 1 DM develops in adults. Adults with LADA are frequently initially
misdiagnosed as having type 2 DM, based on age rather than etiology.
2. Drugs used to treat diabetes:
Biguanide: Biguanide reduce hepatic glucose output and increase uptake of glucose by the periphery,
including skeletal muscle. Although it must be used with caution in patients with impaired liver or
kidney function, metformin, a biguanide, has become the most commonly used agent for type 2 diabetes
in children and teenagers.
Eg: Metformin, Phenformin, Buformin.

INTRODUCTION
Thiazolidinediones: Thiazolidinediones (TZDs), also known as "glitazones," bind to PPAR, a type of

nuclear regulatory protein involved in transcriptionof genes regulating glucose and fat metabolism.
These PPARs act on peroxysome proliferator responsive elements (PPRE). The PPREs influence
insulin-sensitive genes, which enhance production of mRNAs of insulindependent enzymes. The final
result is better use of glucose by the cells. Eg: Rosiglitazone, Pioglitazone, Troglitazone.
Sulfonylureas: Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are useful only in Type II
diabetes, as they work by stimulating endogenous release of insulin.
First-generation agents : Tolbutamide ,Acetohexamide, Tolazamide , Chlorpropamide .
Second-generation agents: Glipizide (Glucotrol), Glyburide or glibenclamide, Glimepiride, Gliclazide,
Glycopyramide, Gliquidone.
Nonsulfonylurea secretagogues:
Meglitinides: Meglitinides help the pancreas produce insulin and are often called "short-acting
secretagogues." They act on the same potassium channels as Sulfonylureas, but at a different binding
site. By closing the potassium channels of the pancreatic beta cells, they open the calcium channels,
thereby enhancing insulin secretion.
Eg: Repaglinide , Nateglinide.
Alpha-glucosidase inhibitors: Miglitol (Glyset), Voglibose, Acarbose (Precose/Glucobay).
Peptide analogs: Exenatide, Liraglutide, Taspoglutide
Dipeptidyl Peptidase-4 Inhibitors: Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin, Allogliptin,
Septagliptin23.

AIM &OBJECTIVE
AIM AND OBJECTIVES

AIM:
Formulation and evaluation of the Anti-diabetic osmotic tablets using controlled porosity osmotic
pump technology.
OBJECTIVES:
1. Selection of drug and suitable polymers.
2. To perform the drug excipient interaction studies.
3. Preparation of tablets by using various proportions of osmogents and selected coating polymers of
cellulose acetate and polyethylene glycol. To study the effect of osmogen on drug release.
4. To perform stability data for optimized formula for 3 months.
5. To check the reproducibility of optimized formulation.
NEED FOR THE STUDY:
Osmotic technology is used preferably to deliver some drugs with short half-life and which are to be
given frequently for chronic ailments, in the form of controlled release formulations. The majority of
existing oral controlled release systems are matrix based, and their principle drug release mechanism
is based on drug diffusion through the matrix system. The diffusion is altered by the pH of the
medium, the presence of food, hydrodynamic conditions, and the bodys other physiological factors,
all of which can cause difficulty in controlling the drug release rate and result in poor invitro, invivo
correlation. Osmotic drug delivery system, which utilizes the principle of osmotic pressure for the
controlled delivery of active agent. The release rate of drug from these systems is independent of the
physiological factors of the gastrointestinal tract to a large extent. Advantages include:
The delivery rate of zero- order (which is most desirable) is achieved with osmotic systems.
Both in vitro and in vivo experiments have established this fact.
Delivery may be delayed of pulsed, if desired.
For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic
conditions.
Higher release rates are possible with osmotic systems compared withconventional diffusion
controlled released drug delivery systems
The release rate of osmotic systems is highly predictable and can be preprogrammed by
modulating the release control parameter.

AIM &OBJECTIVE
A high degree of IVIVC is obtained in osmotic system.

The release from osmotic systems is minimally affected by the presence of food in the
gastrointestinal tract (GIT).
These advantages are attributed to the design of osmotic systems Environmental contents (e.g. GIT
fluids) do not gain access to the drug until the drug has been delivered out of the device.

PLAN OF WORK
PLAN OF WORK
It was planned to carryout study in the sequences below,
1. Pre formulation studies,

Drug excipients interaction studies
2. Formulation of Glipizide osmotic pump drug release tablets using polymers in
different ratios of push layer and pull layers followed by wet granulation,
compression, coating , laser drilling and film coating techniques.
3. Evaluation of blend characteristics/ pre compression characteristics of Glipizide
osmotic pump drug release tablets.
Angle of repose
Bulk density
Tapped density
Compressibility index/ Carrs index
Hausners ratio
4. Evaluation of post compression characteristics of Glipizide osmotic pump drug
release tablets.
Hardness
Friability
Weight variation
Thickness
% Drug content/content uniformity
In-vitro release study/dissolution
5. Selection of best formulation on the basis of invitro drug release.
6. Determining the order of drug release from matrix tablets and mechanism of drug
release.
7. Comparison of Best Formulation with Marketed product.
8. Stability studies of optimised formulation.

LITERATURE SURVEY
LITERATURE SURVEY
Kambham venkateshwarlu et al., Matrix tablets of Glipizide with combination of hydrophobic
polymers Eudragit RL100 (Powder form) and Ethyl cellulose were developed by direct compression
method. In this formulation the effect of polymer concentration on drug release was studied. As the
concentration of Ethyl cellulose increased drug release decreased and when the MCC concentration
increased drug release increased24.
Anil Chaudhary et al., Micro porous bilayer osmotic tablet for colonspecific delivery. Micro
porous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was
developed using a new oral drug delivery system for colon targeting. The tablets were coated with
microporous semi permeable membrane and enteric polymer using conventional pan-coating
process. In vitro dissolution results indicated that system showed acid-resistant, timed release and
was able to deliver drug at an approximate zero order up to 24 h. The developed tablets could be
effectively used for colon-specific drug delivery to treat Irritating bowel syndrome25.
Vamshi Krishna Lekkala et al., Developed Elementary Osmotic Pump (EOP) tablets of metformin
Hcl. Linear and reproducible release similar to that of Fortamet ER 1000 mg tablets was achieved
for optimized formulation (f2 >50) independent of hydrodynamic conditions. The effect of different
formulation variables, namely, ratio of drug to osmogen, membrane weight gain, and level of pore
former on the in vitro release was studied. The drug release by Metformin Hcl ER tablets by osmotic
technology is around 85% in 20 hrs. The optimized formulations were subjected to stability studies
as per International Conference on Harmonization (ICH) guidelines and formulations were stable
after a 3 month study26.
R. Kumaravelrajana et al., Simultaneous delivery of Nifedipine and Metoprolol tartarate using
sandwiched osmotic pump tablet system. It is developed in order to reduce the problems associated
with multidrug therapy of hypertension. This system composed of a middle push layer and attached
drug layers of Nifedipine and Metoprolol. The tablets are prepared by wet granulation technique.
Polyethylene oxide 600,000 and 8,000,000 g/mole were used as thickening agent of drug layer and
the expandable hydrogel of push layer, respectively. It has been observed that amount of
polyethylene oxide (PEO) and KCL of the drug and push layer had profound influence on Nifedipine
and Metoprolol release. Further, the release of drugs was optimized by the size of the delivery
orifice, level of plasticizer and membrane thickness. The optimal osmotic pump tablet was found to
deliver both drugs at a rate of approximately zero order for up to 16 h independent of pH and

LITERATURE SURVEY
agitational intensity, but dependent on the osmotic pressure of the release media. Further sandwiched
system had a good sustained effect in comparison with the conventional product. Hence the
prototype design of the system could be applied to other combinations of drugs used for
cardiovascular diseases, diabetes27.
Ritesh B. Patel et al., Developed osmotic pump tablets (OPT) of glipizide (GLZ) and optimized the
formulation using response surface methodology. The complex of GLZ and HP--CD were prepared
and studied the effects of different ratio of drug to HP--CD and preparation methods on complex
formation. The effects of the osmogen, diameter of the drug releasing orifice, and coating
composition on the drug release profile were investigated during the preliminary trials. Response
surface methodology was used to optimize the OPT. In-vitro drug release profiles from osmotic
tablet were compared with theoretical release profile and statistically analyzed to examine suitability
of OPT for once a day administration. Complex prepared using solvent evaporation method in ratio
of 2:1 showed good solubility and dissolution enhancement. The release from the optimized
formulations was independent of pH and agitation intensity of the release media, assuring the release
to be fairly independent of pH and hydrodynamic conditions of the body. The drug release from OPT
with the optimized formulation showed a controlled release pattern28.
N.G.Raghvendra Rao et al., Prepared controlled zero order release glipizide bilayer matrix tablets
using HPMC, Xanthan gum ,Guar gum ,Karaya gum. Effect of polymer concentration and polymer
blend were studied. It was observed that tablets containing polymer blend of HPMC-Ethyl cellulose
were successfully sustained the drug release up to 12 hours29.
Longxiao L et al., developed a bilayer-core osmotic pump tablet (OPT) which does not require laser
drilling to form the drug delivery orifice is described. The bilayer-core consisted of two layers: (a)
push layer and (b) drug layer, and was made with a modified upper tablet punch, which produced an
indentation at the center of the drug layer surface. Nifedipine was selected as the model drug. The
indented core tablet was coated by ethyl cellulose as semipermeable membrane containing
polyethylene glycol 400 for controlling the membrane permeability. It was found the optimal OPT
was able to deliver nifedipine at an approximate zero-order up to 24 hrs, independent on both release
media and agitation rates. The preparation of bilayer core OPT was simplified by coating the
indented core tablet, by which sophisticated technology of the drug layer identification and laser
drilling could be eliminated30.
Shokri J. et al., Developed a new type of elementary osmotic pump (EOP) tablet for efficient
delivery o f poorly water-soluble/practically insoluble drugs. Drug release from the system, called
LITERATURE SURVEY
swellable elementary osmotic pump (SEOP), I through a delivery orifice in the form of a very fine
dispersion ready for dissolution and absorption. The release behavior of indomethacin from different
formulations of this dosage form was studied at pH 6.8 for a period of 24 h. The formulations were
compared based on four comparative parameters, namely, D24h (total release after 24 h), tL (lag
time), RSQ zero (R square of zero order equation) and D% zero (percentage deviation from zero
order kinetics). The results showed that concentration of wetting agent in the core formulation was a
very important parameter in D24h and release pattern of indomethacin from SEOP system.
Increasing the amount of wetting agent to an optimum level (60 mg) significantly increased D24h
and improved zero order release pattern of indomethacin. Increasing concentration of castor oil
(hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in
diameter for the formulations studied here was determined to be 650 m for zero order release
pattern. tL and D% zero were dramatically decreased whereas D24h and RSQ zero increased with
increasing the aperture size to optimum level31.
Reza fassihi et al., Prepared monolithic matrix system of glipizide tablets by using the swellable
hydroxypropylmethylcellulose (HPMC) or erodible polyethylene oxide (PEO). In this study linear
release of glipizide, similar to the profile of the commercial PPOP system, Glucotrol XL. The
interrelationship between matrix hydration, erosion and textural properties were determined and
analyzed under the dissolution test conditions. HPMC matrices showed a significantly greater degree
of hydration and swelling and stronger texture property relative to PEO matrices. Resultsindicate that
in the case of low dose/low soluble drug, total drug release in a zero order manner heavily depends
on the synchronization of erosion and swelling fronts during the entire dissolution study32.
Vincent Malaterre et al., Prepared a simple elementary osmotic pump (EOP)system that could
deliver metformin hydrochloride (MT) and glipizide (GZ) simultaneously for extended periods of
time was developed in order to reduce the problems associated with multidrug therapy of type 2 non-
insulin-dependent diabetes mellitus. Good sustained effect in comparison with the conventional
product. The prototype design of the system could be applied to other combinations of drugs used for
cardiovascular diseases, diabetes, etc33.
Suresh P. Vyas et al., studied an oral osmotic system which can deliver theophylline and
Salbutamol sulphate simultaneously for extended period of time. A modified two layered, pushpull
osmotic system was developed by using the basic designs of various oral osmotic pumps, such as
controlled porosity osmotic pump (CPOP), elementary osmotic pump (EOP) and pushpull osmotic

LITERATURE SURVEY
pump (PPOP). Cellulose acetate solution with 25% (w/w) of sorbitol can be used as an optimized
concentration of pore forming agent with 25% (w/w) of plasticizer, which was keep constant34.
Thombre AG et al., studied a controlled porosity osmotic pump-based drug delivery system.
Pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for
a period of 12 h. Sodium bicarbonate was used as the osmogen. The effect of different ratios of drug:
osmogen on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable
membrane. Different channeling agents tried was diethyl phthalate (DEP), dibutylphthalate (DBP)
dibutylsebacate (DBS) and polyethylene glycol 400 (PEG 400). It was found tha drug release rate
increased with the amount of osmogen due to the increased water uptake and hence increased driving
force for drug release. This could be retarded by the proper choice of channeling agent in order to
achieve the desired zero order 35.

MATERIALS AND METHODS

5.1 MATERIALS
Table No: 5 List of materials used in formulations
S.NO MATERIAL SOURCE
1 Glipizide Hetero labs Ltd., Jedcherla
2 Polyox WSR coagulant Aqalon

3 Ferric oxide Red Fe203 Hetero labs Ltd., Jedcherla
4 Polyox WSR coagulant 301 Aqalon
5 Sodium chloride Hetero labs Ltd., Jedcherla
6 Magnesium stearate Hetero labs Ltd., Jedcherla
7 Acetone S,D Fine chemicals, Mumbai
8 Methanol S,D Fine chemicals, Mumbai
9 Potassium di hydrogen
Hetero labs Ltd., Jedcherla
10 Phosphate
Sodium hydroxide Hetero labs Ltd., Jedcherla
11 Hydrochloric acid S,D Fine chemicals, Mumbai
12 Cellulose acetate S,D Fine chemicals, Mumbai

DRUG PROFILE36
Drug name: Glipizide
Chemical Name: 1-cyclohexyl-3-[[p-[2-(5-ethylpyrazinecarboxamido) ethyl] phenyl]
sulfonyl] urea
Chemical formula: C21H27O5S4
Molecular Weight: 445.54
Chemical structure:
Fig 5 Chemical structure of Glipizide

Category: Antidiabetic
Description: A white powder.
Solubility: Practically insoluble in water and ethanol, soluble in chloroform,Di methyl formamide, and in
dilute solution of alkali hydroxides, sparingly soluble in acetone.
Mechanism of action:
The primary mode of action of Glipizide in experimental animals appears to be the stimulation of insulin
secretion from the beta cells of pancreatic islets tissue and is thus dependant on functioning beta cells in
the pancreatic islets. In human Glipizide appears to lower the blood glucose acutely by stimulating the
release of insulin from the pancreas, an effect dependent upon functioning beta cell in the pancreatic islet.
In man stimulation of insulin secretion by Glipizide in response to a meal is undoubtedly of majo
importance. Fasting insulin levels are not elevated even on long term Glipizide administration, but the
postprandial insulin response continues to be enhanced after at least six months of treatment. The insulin
topic response to a meal occurs within 30 minutes after an oral dose of Glipizide in diabetic patients, but
elevated insulin levels do not persist beyond the time of the meal challenge. Extra pancreatic effects may
play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Beginning 2 to 3 hours
after the administration of Glipizide sustained release, plasma concentration of Glipizide gradually
rise reaching to a maximum concentration within 3 to 8 hours after dosing. With subsequent once

daily dosing of Glipizide sustain release, effective plasma concentrations are maintained throughout
24 hours period with fewer peaks to trough fluctuations. In view of the time required to reach an
optimal concentration in plasma, drug may be more effective when given 30 minutes before eating.
Drug in plasma 98.3% bound to plasma protein especially with albumin. Drug is metabolized in
liver, and the metabolites are excreted in urine. Less than 5 % drug excreted unchanged in urine.
Pharmacokinetics:
Glipizide is completed and rapidly absorbed ensuring prompt and constant activity Peak plasma
concentrations are attained within 1.5-2.0 hours after a single oral dose. The half-life of elimination
ranges from 2 to 3 hours. The drug is excreted in the urine as virtually inactive metabolites. When
taken before each meal, glynase controls postprandial hyperglycemia without the risk of delayed
episodes of hypoglycaemial. Dependent Diabetes Mellitus where diet control alone is not effective in
controlling the hyperglycemia. Dosage should be adapted to patients individually, on basis of
periodic tests of glycosuria and blood sugar. The maximum daily dose should not exceed 10 mg.
Contraindication:
Like other sulfonylureas, Glipizide is contraindicated in: Insulin dependent diabetes mellitus,
diabetic-keto-acidosis, diabetic coma, pregnancy, subjects with severel impaired kidney or liver
function, adrenal insufficiency and cases of confirme individual hypersensitivity to the drug. In latent
diabetes or prediabetic states, the use of sulfonylurea is not advisable.
Interaction:
The hypoglycemic actions of sulfonylurea may be potentiated by certain drugs including
nonsteriodal anti-inflammatory drugs and other drugs that are highly protein bound salicylates,
sulphonamides, and chlormphenicol. When such drugs are administered to a patient receiving
Glipizide, the patient should be observed for hypoglycemia.
Side effects:
Hypoglycemia, Gastrointestinal disturbances, allergic reactions including erythema, urticaria.
Precaution:
Patients should be instructed to closely follow their physicians prescription as regards diet, dosage
and schedule for taking the drug, and should be taught to recognize promptly the early symptoms of
hypoglycemia, that generally are headache, irritability, sleep disorders, tremor and heavy sweating,
so they can contact a doctor in good time.

Table No: 6 Pharmacokinetic parameters of Glipizide
Pharmacokinetic parameters Value

Fraction of drug absorbed (f) 1
Elimination half-life (t 1/2) 3.8h

Terminal disposition rate Constant kel 0.21 h-1
Apparent volume of distribution (V d) 0.17 l/kg
Minimum effective concentration (C ss 20 ng/ml

min)
Maximum effective concentration 300 ng/ml
(Cssmin)
Clearance (CL) 0.52 + 0.18 ml
min-1 kg -1
No well-defined upper limits reported for therapeutically effective plasma concentration. However,
threshold concentration of 300 ng/ml has been suggested above which no additional glucose-
lowering effect is likely to be achieved.

EXCIPIENT PROFILE37
POLYETHYLENE OXIDE
Synonyms
Polyox; polyoxirane; polyoxyethylene.
Chemical Name and
Polyethylene oxide
Structural Formula
The USPNF 23 describes polyethylene oxide as a nonionic homopolymer of ethyleneoxide,

represented by the formula (CH2CH2O)n, where n represents the average number of oxyethylene
groups. It may contain up to 3% of silicon dioxide.
Functional Category
Mucoadhesive; tablet binder; thickening agent.
Applications in Pharmaceutical Formulation or Technology
Polyethylene oxide can be used as a tablet binder at concentrations of 585%. The higher molecular
weight grades provide delayed drug release via the hydrophilic matrix . The relationship between
swelling capacity and molecular weight is a good guide when selecting products for use in
immediate- or sustained-release matrix formulations; Polyethylene oxide has been shown to be an
excellent mucoadhesive polymer. Low levels of polyethylene oxide are effective thickeners,
although alcohol is usually added to waterbased formulations to provide improved viscosity stability;
Polyethylene oxide films demonstrate good lubricity when wet. This property has been utilized in the
development of coatings for medical devices. Polyethylene oxide can be radiation crosslinked in
solution to produce a hydrogel that can be used in wound care applications.
Description
White to off-white, free-flowing powder. Slight ammoniacal odor.

CELLULOSE ACETATE :
Synonyms: Acetyl cellulose, cellulose diacetate, cellulose triacetate
Molecular formula: Cellulose acetate is cellulose in which a portion or all of the hydroxyl groups
are acetylated. Cellulose acetate is available in a wide range of acetyl levels and chain lengths and
thus molecular weight.
Description: It occur s as a white to off white powder, free flowing pellets, or flakes. It is tasteless
and odorless or may have a slight odor of acetic acid.
Functional category: Coating agent, extended release agent, tablet and capsule diluents
Applications in pharmaceutical formulation:
It is used as a semi permeable coating on tablets, especially on osmotic pump-type tablets and
implants. This allows for controlled, extended release of actives. Cellulose acetate films, in
conjunction with other materials, also offers sustained release without the necessity of drilling a hole
in the coating as is typical with osmotic pump systems.Cellulose acetate films have also been used in
transdermal drug delivery studies. Also used as a film coating on tablet or granules for taste masking.
Solubility: cellulose acetates are soluble in acetone; water blends o f varying ratios, methylene
chloride, ethanol blends, dimethylformamide, and dioxane.
Stability and storage condition: It is stable if stored in a well closed container in a cool and dry
place. Cellulose acetate hydrolyzes slowly under prolonged adverse conditions such as high
temperature and humidity.
Incompatibilities:It is incompatible with strongly acidic or alkaline substances. Cellulose acetate is
compatible with the following plasticizers: triacetin, triethyl citrate, dimethyl phthalate, and
polyethylene glycol.
Safety: It is widely used in oral pharmaceutical products and it generally regarded as a nontoxic and
nonirritant material.

POLYETHYLENE GLYCOL:
Synonyms: Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; macrogola; PEG;Pluriol E;
polyoxyethylene glycol.
Chemical Name: -Hydro- hydroxypoly(oxy-1,2-ethanediyl).
Molecular Formula: HOCH2(CH2OCH2)mCH2OH where m represents the average number of
oxyethylene groups.
Fig. 6 Chemical structure of Polyethylene Glycol

Description: Polyethylene glycol as being an addition polymer of ethylene oxide and water.
Polyethylene glycolgrades 200600 are liquids; grades 1000 and above are solids at ambient
temperatures. Liquid grades (PEG 200600) occur as clear, colorless or slightly yellow-colored,
viscous liquids. They have a slight but characteristic odor and a bitter, slightly burning taste. PEG
600 can occur as a solid at ambient temperatures. Solubility: All grades of polyethylene glycol are
soluble in water and miscible in all proportions with other polyethylene glycols (after melting, if
necessary).
Functional Category: Ointment base; plasticizer; solvent; suppository base; tablet and capsule
lubricant.
Applications in Pharmaceutical Technology:Polyethylene glycols are stable, hydrophilic
substances that are essentially nonirritant to the skin, it is used as a ointment bases Solid grades are
generally employed in topical ointments, Mixtures of polyethylene glycols can be used as
suppositorybases,for which they have many advantages over fats. For example, the melting point of
the suppository can be made higher to withstand exposure to warmer climates; release of the drug is
not dependent upon melting point; the physical stability on storage is better; and suppositories are
readily miscible with rectal fluids In concentrations up to approximately 30% v/v, PEG 300 and PEG
400 have been used as the vehicle for parenteral dosage forms.

SODIUM CHLORIDE:
Synonyms: Alberger; chlorure de sodium; common salt; hopper salt; natrichloridum; natural halite;
rock salt; saline; salt; sea salt; table salt.
Molecular Formula: NaCl
Molecular Weight: 58.44
Functional Category: Tablet and capsule diluent; tonicity agent.
Description: Sodium chloride occurs as a white crystalline powder or colorless crystals; it has a
saline taste. The crystal lattice is a face centered cubic structure. Solid sodium chloride contains no
water of crystallization although, below 8o C, salt may crystallize as adihydrate.
Applications in Pharmaceutical Technology:
Sodium chloride is widely used in a variety of parenteral and nonparenteral pharmaceutical
formulations, where the primary useis to produce isotonic solutions.Sodium chloride has been used
as a lubricant and diluents in capsules and direct-compression tablet formulations in the
past,although this practice is no longer common. Sodium chloride hasalso been used as a channeling
agent and as an osmotic agentin the cores of controlled-release tablets.
Table No:7 Uses of Sodium chloride
Use Concentration (%)

Capsule diluents 1080
Controlled flocculation of suspensions 41
Direct compression tablet diluents 1080
To produce isotonic solutions in 40.9
intravenous or
ophthalmic preparations 5-20
Stability and Storage Conditions:

Aqueous sodium chloride solutions are stable but may cause the separation of glass particles from
certain types of glass containers. Aqueous solutions may be sterilized by autoclaving or filtration.
The solid material is stable and should be stored in a well closedcontainer, in a cool, dry place. It has
been shown that the compaction characteristics and themechanical properties of tablets are
influenced by the relative humidity of the storage conditions under which sodium chloridewas kept.

Incompatibilities:
Aqueous sodium chloride solutions are corrosive to iron. They alsoreact to form precipitates with
silver, lead, and mercury salts. Strongoxidizing agents liberate chlorine from acidified solutions of
sodiumchloride. The solubility of the antimicrobial preservative methylparabenis decreased in
aqueous sodium chloride solution andthe viscosity of carbomer gels and solutions of
hydroxyethylcellulose or Hydroxypropyl cellulose is reduced by the addition of sodium chloride.

Table No: 8 List of Equipments and instruments
S.NO INSTRUMENT NAME MANUFACTURER
1 Semi micro balance Sartorius
2 Rapid mixer dryer Retsch TG 200
3 LOD apparatus Sartorius
4 Double sided rotary tablet press Cadmach
5 Hardness tester Pharmag instruments
6 Vernier calipers Pharmag instruments
7 Friabilator Eletrolab(USP)
8 Coating machine Neocota
9 Dissolution apparatus Electro lab(USP)
10 Tapped density apparatus Electro lab(USP)
11 Particle size distributer Retsch AS 200
12 UV-visible Spectrophotometer Shimadzu 1700
13 Laser Drilling Machine Scantech

METHODOLOGY
5.1 ANALYTICAL METHODS38:
1. Preparation of Buffer and Reagent:
Phosphate buffer solution, pH 7.5: 6.8gm of potassium dihydrogen phosphate was placed in a 1000
ml volumetric flask, dissolved with distilled water and the final pH was adjusted with 0.2N sodium
hydroxide solution.
2 Determination of max of the drug: Glipizide was dissolved in pH 7.5 phosphate buffer solution
[PBS] and further diluted with the same and scanned for maximum absorbance in double beam UV-
visible spectrophotometer in the range from 200 to 400 nm, using PBS pH 7.5 as blank. The max of
the drug was found to be at 222 nm.
3.Standard curve of glipizide in phosphate buffer (pH 7.5): 100 mg of Glipizide was accurately
weighed and dissolved in 100 ml of PBS to prepare stock solution. The aliquot amount of stock
solution was further diluted with PBS pH 7.5 to get 2 g/ml, 4 g/ml, 6 g/ml, 8 g/ml, 10 g/ml
and 12 g/ml of the final drug solution. Then the peak area was measured by UV method of analysis
at max 222nm.
5.2 PREFORMULATION STUDIES:
1. Drug Excepients Interaction Studies:
Drug excepients interaction studies were studied by using FTIR spectroscopic studies to study the
interaction studies following combinations were used.
1. Pure Drug
2. Pure Drug with polymers .
Table No: 9 The FTIR spectra of pure drug were observed for peaks at wave Numbers
Type of stretching wave number
-c=o, urea stretching 1653 cm-1
Cyclohexyl stretching 1157 cm-1
SO2NH stretching 1331 cm-1

CONH stretching 1637 cm

2 Determination of melting point: Melting point was determined by taking small amount of
Glipizide in a capillary tube closed at one end. The capillary tube was placed in an electrically
operated melting point apparatus and the temperature at which the drug melts was recorded. This
was performed thrice and average value was noted.
3 Saturation solubility of drug in PBS pH 7.5:
Excess of drug (approximately 100 mg) was added in 30 ml of glass vial containing 10 ml of water
and buffer solutions of different pH. All the vial were screw capped tightly and kept for shaking (at
160 rpm) on a shaking water bat at 37 C for 48 h. The samples were kept undisturbed for 12 h at the
same temperature and then filtered through 0.22 micron nylon membrane filter Samples were
analyzed at max 225 nm after suitable dilutions.
5.3 FORMULATION DEVELOPMENT:
Preparation of Glipizide tablets:
Push layer
Drug layer composed of Glipizide, Polyox WSR coagulant and Lactose are weighed accurately and
passed through 40#. The mixed powder was granulated with ethanol. Wet mass dried in Fluidized
bed dryer at 250c, 15 amp airflow for 15 minutes.
Pull layer
Pull layer composed of Sodium chloride, Polyox WSR coagulant 301, Ferric oxide red Fe203 passed
through 60# and mixed properly. The mixed powder was granulated with ethanol. Wet mass dried in
Fluidized bed dryer at 250c, 15 amp airflow for 15 minutes.
After drying two layers are lubricated with magnesium stearate which passed through 60#. Blend it
in a blender for 5 minutes. The prepared blend was placed in die cavity and compressed with
hardness 3.2-4 kp with diameter 3.68 mm by 8 mm round standard concave punches with machine
by bi layer tablet method.

Table No: 10 Formulation table of the Glipizide osmotic controlled release tablets
s.no. Ingredients F1 F2 F3 F4 F5 F6 F7
1 core tablet
Glipizide mg/un
10 mg/unit
10 mg/unit
10 mg/unit
10 mg/unit
10 mg/unit
10 mg/unit
10
Polyox WSR it
coagulant
2 86 86 86 86 86 86 86
3 Ethanol q.s q.s q.s q.s q.s q.s q.s
4 Sodium chloride 30 30 30 50 50 70 70
5 Polyox WSR 70 70 70 50 50 30 30
coagulant 301
6 Ethanol q.s q.s q.s q.s q.s q.s q.s
7 Ferric oxide red 2 2 2 2 2 2 2
Magnesium
8 Stearate 2 2 2 2 2 2 2
core tablet
weight (mg) 200 200 200 200 200 200 200
coating(3% w/w)
9 Cellulose acetate ** 4.2 3 4.2 3 4.2 3

Polyethylene 70:30 50:50 70:30 50:50 70:30 50:50
10 Glycol ** 1.8 3 1.8 3 1.8 3
11 Acetone ** q.s q.s q.s q.s q.s q.s

12 Purified water ** q.s q.s q.s q.s q.s q.s
Film coating 1% ** 1% 1% 1% 1% 1% 1%
w/w
13 Opadry white ** 2 2 2 2 2 2
14 Purified water ** q.s q.s q.s q.s q.s q.s
Coated tablet
weight (mg)
** 208 208 208 208 208 208

5.4 COATING OF TABLETS

1. Preparation of coating solution:
The coating material consist of 3%w/w of the solution, the solution consist cellulose acetate and
polyethylene glycol 400 (in 70:30 and 50:50 ratio), cellulose acetate act as semi permeable
membrane polyethylene glycol 400 act as plasticizer. These materials are dissolved in acetone &
water (in 9:1 ratio). Acetone was taken in a beaker and in kept magnetic stirrer while stirring the
cellulose acetate was added and the stirring was continued for 15min the cellulose acetate was
completely dissolved. The same procedure followed to water &PEG 400 for 15min, PEG 400 was
dissolved in water, above solution was added to cellulose acetate solution and kept for 15min
stirring. While coating the material was wasted for this reason we take 50% extra coating material.
Before applying coating solution, all weighed tablets put in coating pan and pre -warming for 15min
in this time the bed temperature (28-30oC) was maintained and collect the some tablets and
average weight of the tablets was measured. Spray the coating solution on tablets through spray gun
and also supply hot air to dry the tablets. During this procedure coating pan rotated continuously.
This process is continued for required percentage of weight gain up to 12%. After coating the
solution spray was stopped and tablets kept 15min for post warming. Dry tablets are weighed and
the average weight was determined. The % of weight gain was calculated by following equation.
% weigh gain = (Wt-Wo/ Wo) *100
Where,
Wt = weight of tablet after coating
Wo = weight of tablet before coating
Table No: 11 Coating composition for 3% weight gain.
Material Weight (grms)

Cellulose acetate 22.75
PEG 400 9.75
Acetone 945.72
Water 105.08

Table No: 12 Coating machine (NEO COTA) process parameters and its limits.
S.no Process parameter Limit
1 Bed temperature 28-30oC

2 Inlet temperature 20-25oC
3 Exhaust temperature 30oC
4 Atomization pressure 1.5 0.8 atm
5 Pan rpm 5-8rpm
6 Spray rpm 5-15rpm
7 Distance between spray gun 10-15cm

and tablets bed
and tablet bed
Fig. 7 Coating machine (Neocoata)

5.5 LASSER DRILLING OF COATED TABLETS:
The coated tablet drill in depth 0.5 mm and width 0.5 mm to the pull layer of the coated tablet for the
purpose of push and pull layer mechanism.
5.6 FILM COATING OF DRILLED TABLETS:
The coating material consist of 1%w/w of the solution, the solution consist opadry white purified water
as solvent. purified water was taken in a beaker and in kept magnetic stirrer while stirring the opadry
white was added and the stirring was continued for 15min. Before applying coating solution, all weighed
tablets put in coating pan and pre -warming for 15min in this time the bed temperature (28-30oC) was
maintained and collect the some tablets and average weight of the tablets was measured. Spray the
coating solution on tablets through spray gun and also supply hot air to dry the tablets. During this
procedure coating pan rotated continuously. This process is continued for required percentage of weight
gain up to 12%. After coating the solution spray was stopped and tablets kept 15min for post warming.
Dry tablets are weighed and the average weight was determined. The % of weight gain was calculated by
following equation.
% weigh gain = (Wt-Wo/ Wo) *100
Where,Wt = weight of tablet after coating
Wo = weight of tablet before coating
Table No: 13 Coating machine (NEO COTA) process parameters and its limits
S.no Process parameter Limit

1 Bed temperature 28-300c
2 Inlet temperature 20-25oC
3 Exhaust temperature 30oC
4 Atomization pressure 0.8 1.5 atm
5 Pan rpm 5-8 rpm
6 Spray rpm 5-15 rpm
7 Distance between spray gun 10-15cm
and tablet bed

and tablet bed
5.7 PRE-COMPRESSION PARAMETERS39

Flow properties of prepared granules:
The quality of tablet, once formulated by rule, is generally dictated by the quality of
physicochemical properties of blends. There are many formulations and process variables involved
in mixing and all these can affect the characteristics of blends produced.
The various characteristics of blends tested are as given below.
Bulk Density; An accurately weighed (10gr) quantity of powder was transferred to a 100ml
measuring cylinder and the volume occupied by the powder in terms of ml was recorded.
Weight of powder in gm.
Bulk Density = ---------------------------------
Volume of powder in ml
Tapped bulk Density: The loosely packed powder in the measuring cylinder was tapped by USP
type II apparatus. Initially 500 times tapped and then go for 750 taps. If volume difference is more
than 2% between the 500& 750 taps then go for 1000taps. This procedure continued until the
consecutive difference between the taps is below or equal to 2% and finally measure the powder
volume
TBD - LBD
Tapped bulk density = --------------------- 100
TBD
Hausners ratio: The Hausners ratio of the drug and granules was determined by following equation it
was used to predict powder flow properties.
Hausners ratio = (TBD/LBD)
Carrs Compressibility Index: (Subramanyam CVS et al., 2005)

TBD - LBD
Percent Carrs Index = --------------------- 100
TBD
Angle of Repose: It is measured to find frictional forces in loose powder or granules. It is the
maximum angle possible between the surface of a pile of powder or granules and horizontal plane.

Where,
h = the height of the powder cone
r = the radius of the powder cone
Flow properties for different values of angle of repose are given below
Table No: IP limits for flow properties
S.no Powder flow Angle of Repose Carrs index Hausners ratio
1 Excellent < 25 < 10 1.00 1.11

2 Properties
Good 25 30 11 15 1.11 1.18
3 Fair _ 16 20 1.19 1.25
4 Possible 30 40 21 25 1.26 1.34
5 Poor --- 26 31
6 Very poor 40 32 37 1.35 1.45
7 Very very poor --- > 38 >1.60
5.8 EVALUATION OF PREPARED CORE TABLETS40: The tablets were evaluated

for in process and finished product quality control tests i.e. appearance, dimensions (diameter and
thickness), weight variation, hardness, and friability.
Appearance: The core tablets were checked for presence of cracks, depressions, pinholes,
uniformity of the color, smooth polish on the surface of tablet etc if any.
Dimensions: Thickness and diameter of core tablets were measured using Verniar calipers. These
values were checked and used to adjust the initial stages of compression.
Uniformity of Weight (Weight variation test): This is an important in-process quality control
(IPQC) test to be carried out frequently. Corrections in weight variation were made during the
compression process of tablets. Any variation in the weight of tablet (for any reason) leads to either
under medication or overdose. So, every tablet in each batch should have a uniform weight.

Table No: 15 Pharmacoepial specifications for tablet weight variation
Average weight of Average weight of tablet Maximum percentage

tablet deviation allowed
Less than 80 Tablets

Less(mg)
than (130
U.S.P ) 10
Tablets (mg) ( I.P )
80-250 130-324 7.5
More than 250 More than 324 5
20 tablets were weighed individually and average weight was calculated from the total weight of 20
tablets. The individual weights were compared with the permissible limits (5 %). The percent
deviation was calculated using the following formula
Individual weight average weight
Percentage Deviation = --------------------------------------------- x 100
Average weight
Hardness test: 6 Tablets were randomly selected from each batch and hardness of each tablet was
determined by using a Pharmag instruments.
Friability test: It is the ability of tablets to withstand mechanical shocks during handling and
transportations 6.5gr of tablets were picked from each batch and weighed and placed in the Rochae
friability test apparatus and operated at rate of 25 RPM for 4 minutes (or up to 100
revolutions),tablets were de-dusted and weighed again. The loss of tablet weight due to abrasion and
fracture was measured in terms of % friability (A value of <1%F is acceptable).
Initial wt final wt
F = -------------------------- 100
Initial wt

Drug content estimation: The Glipizide tablets were tested for their drug content. Five tablets were
finely powdered required quantities of the powder equivalent to 10 mg of Glipizide were accurately
weighed and transferred to a 100ml of volumetric flask. The flask was filled with Phosphate buffer
(pH 7.5) solution and mixed thoroughly. The solution was made up to volume and filtered. Dilute 10
ml of the resulting solution to 200 ml with Phosphate buffer (pH 7.5) and measure the absorbance of
the resulting solution at the max 222 nm using a UV spectrophotometer. The linearity equation
obtained from calibration curve as described previously was used for estimation of Glipizide in the
tablet formulations.
In-vitro Dissolution studies:
In vitro drug release studies of the prepared tablets were conducted for a period of 16 hours using an
eight station USP type II apparatus (ELECTROLAB, India) at 370.50C the paddle speed was 50
1 rpm. The dissolution medium used in each flask was 900 ml of buffer media pH 7.5 At different
intervals, 10 ml of samples were withdrawn and filter through a whatman filter paper. The equivalent
volume of the medium was added to the dissolution flask.
Analysis of drug release by UV-Visible spectrophotometer:
The collected samples were filtered and appropriate dilution was done, then the sample solutions
were analyzed at max 222 nm by using double beam U.V/visible spectrophotometer (SHIMADZU-
1700) and dissolution medium as blank. Experiments were performed in triplicates. The amount of
drug present in the samples was calculated with the help of calibration curve constructed from
reference standard.
5.9 COMPARISON OF DISSOLUTION PROFILES41:
Difference factor (f1): Difference factor measures the percent error between two curves over all
time points. N
Where n = sampling number

Rj and Tj are the percent dissolved of the reference and test products at each time point j. The
percent error is zero when the test and the reference profiles are identical and increases
proportionally with increasing dissimilarity between the two dissolution profiles.
Similarity Factor (f2): Similarity factor is a logarithmic reciprocal square root transformation of
one plus the mean squared (the average sum of squares) differences of drug percent dissolved
between the test and the reference products. According to FDA, the two dissolution profiles are
similar if f2 is between 50 and 100.
In general, f1values lower than 15 (0-15) and f2 values higher than 50 (50-100) indicate similarity of
dissolution profiles.
Drug release kinetics: (Brahmankar DM et al., 2005)( Costa P et al.,Pharm Sci 2001)
Zero order kinetics: Drug dissolution from pharmaceutical dosag forms that do not disaggregate
and release the drug slowly (assuming that area does not change and no equilibrium conditions are
obtained) can be represented by the following equation:
W0 Wt = K0t
Where W0 is the initial amount of drug in the pharmaceutical dosage form, Wt is the amount of drug
in the pharmaceutical dosage form at time t and k is proportionality constant. Dividing this equation
by W0 and simplifying:
ft= k0t
Where ft = 1 (Wt / W0 ) and ft represents the fraction of drug dissolved in time t and k0 the
apparent dissolution rate constant or zero order release constant in this way, a graphic of the drug-
dissolved fraction versus time will be linear if the previously established conditions were full filled.
In this way a graphical relationship between ft versus time to get the Zero order constant from the
slope. This relation can be used to describe the drug dissolution of several types of modified release
pharmaceutical dosage forms, as in the case of some transdermal systems as well as matrix tablets
with low soluble drugs (Varelas et al., 1995), coated forms, osmotic systems, etc. the pharmaceutical

dosage forms following this profile release the same amount of drug by unit of time and it is the ideal
method of drug release in order to achieve pharmacological prolonged action.
First order kinetics: This type of model to analyze drug dissolution study was first proposed by
Gibaldi and Feldman and later by Wagner. The relation expressing this model:
Log Qt = Log Q0 + K1t/2.303
Where Qt is the amount of drug released in time t, Q0 is initial amount of drug in the solution and
K1 is the first order release rate constant. In this way a graphical relationship between log percent
drug remaining versus time to get the First order constant from the slope. The pharmaceutical dosage
forms following this dissolution profile, such as those containing water-soluble drugs in porous
matrices release the drug in a way that is proportional to the amount of drug remaining in its interior,
in such a way, that the amount of drug released by unit of time diminishes.
Higuchi Model: (Higuchi 1961, Higuchi 1963, Cobby et al., 1973):
Qt = KHt1/2
Where,
Qt = the amount of drug released at time t and
KH = the Higuchi release rate;
This is the most widely used model to describe drug release from pharmaceutical matrices. A linear
relationship between the square root of time versus the concentration indicates that the drug release
follows strict Fickian diffusion. For purpose of data treatment, the above equation is usually reduced
to:
Q = Kt1/2
Therefore a plot of amount of drug released versus the square root of tim should be linear if drug
release from the matrix is diffusion controlled. Alternatively the drug release rate is proportional to
the reciprocal of the square root of time. An important advantage of the above equations is its
simplicity.
Korsmeyer Peppas model: (Korsmeyer et al., 1983, Peppas 1985 and Harland,1988): Korsmeyer et
al., (1983) developed a simple semi empirical model, relating exponentially the drug release to the
elapsed time (t).
Qt/Q = Kktn

Where Kk is a constant incorporating structural and geometric characteristic of the drug dosage form
and n is the release exponent, indicative of the drug release mechanism. For, an n value of ~0.5
indicates diffusion controlled mechanism while an n value of~1.0 indicates erosion (Ford et al.,
1991) Hariharan et al., 1997 a suggested that if the value of n is 0.5, it indicates Fickian transport, a
value of 0.5 and 1.0 non-Fickian transport, and the values close to 1.0 indicate that the system is
releasing drug in a zero order manner regardless of the actual mechanism of release.
Table No 16: Release mechanism Korsmeyer Peppas kinetic model
Release exponent (n) Drug transport Rate as a function of

mechanism time
0.45 Fickian diffusion t-0.5
0.45<n<0.89 Non-Fickian, tn-1
Anomalous transport
0.89 Case-II transport Zero-order release
Higher than 1.0 Super Case-II transport tn-1
This type of analysis of release behavior is valuable is to the formulator for comparative purposes .
The Release exponent can be obtained from the slope and the Constant (Kk) obtained from the
intercept of the graphical relation between logarithmic versions of left side of the equation versus log
t.

RESULTS AND DISSCUSION
RESULTS
6.1 PREFOMULATION STUDIES:
API evaluation:
a) Organoleptic evaluation:
Table No:17 Organoleptic properties of Glipizide
Properties Results
Description powder
Taste Tasteless
Odour Odourless
Colour Colourless
b) Solubility:
Glipizide practically insoluble in water and ethanol, soluble in chloroform, dimethylformamide, and
in dilute solution of alkali hydroxides, sparingly soluble in acetone.
Standard plot for Glipizide
Table No: 18 Calibration curve of Glipizide
S. No Concentration Absorbance Average

(/ml) absorbance
1 2 3
1 0 0.00 0.00 0.00 0.00
2 (g/ml)
0.7 0.0420 0.0425 0.0422 0.0423
3 1.4 0.070 0.075 0.074 0.073
4 2.8 0.1533 0.1540 0.1538 0.1537
5 5.6 0.2936 0.2938 0.2931 0.2935
6 11.2 0.5916 0.5916 0.5911 0.5915
7 14 0.7402 0.7410 0.7408 0.7406

Fig.8 Calibration curve of Glipizide
Fig. 9 FTIR for Glipizide pure drug

Fig No: 10 FTIR study for drug with Polyox WSR coagulant
6.2. EVALUATION OF MICROMETRICS:

1 Physical properties of Glipizide:
Interparticulate interactions influence the physical properties of powder flow. A comparison of the
bulk density and tapped density can give a measure of the relative importance of this interaction in a
given powder. Such a comparison is often used as an index of the ability of the powder to flow.
Physical properties of Glipizide like bulk density, tapped density, compressibility index, Hausners
ratio, and angle of repose are shown in Table.
Table No:19 Flow properties of Glipizide
S.no Parameter Value Type of Flow
1 Bulk density 0.145 ----

2 Tapped density 0.264 ----
3 Carr`s index 45.07 Very very poor

4 Hausner`s ratio 1.820 Very very poor
5 Angle of repose 43 Very very poor

Table No: 20 Average values of pre-compressive parameters of tablet blend
Formulation Bulk Tapped Carr`s Hausner`s Angle of

Code density density index ratio repose
F1 0.416 0.463 10.1512 1.112 25
(g/ml) (g/ml) (%)
F2 0.403 0.465 13.3333 1.153 27
F3 0.416 0.431 3.4803 1.036 20
F4 0.431 0.468 7.906 1.085 22
F5 0.401 0.449 10.6904 1.119 25
F6 0.398 0.438 9.1324 1.102 24
F7 0.411 0.467 11.9914 1.136 26
6.3 EVALUATION OF CORE TABLETS:

The tablet formulations were subject to various post-compressive evaluation tests, such as, Hardness,
Friability and Weight variation, drug content uniformity.
1 Weight variation test: It was carried out as per official method and the average percentage
deviation of all the formulation was found to be within the limit (as per USP standard).
2 Content uniformity: Was also carried out as per official method and it was found that all batches
shows good content uniformity. The values for all the formulations were in the ranges from 93.22 to
98.44%.
3 Hardness test: States that all the formulations were found in the range 8to 10 kp.
4 Friability test: Compressed tablets have lose less than 1 % of their weight are generally
considered acceptable. All the formulations have less than 1% friability.

Table No: 21 Evaluation results of the compressed tablets
Formu Thickness Weight Hardness Friability Content

-lation variation test (kp) test (%) uniformity
code (mm) (mg) (%)

F1 4.71 0.04 340.2 2.48 9.11 0.27 0.3 94.16 0.49
F2 4.71 0.04 339.7 2.31 9.12 0.34 0.1 94.03 2.13
F3 4.69 0.02 341.1 3.78 9.28 0.16 0.4 96.7 2.32
F4 4.67 0.01 339.7 3.26 9.18 0.33 0.3 97.4 1.51
F5 4.71 0.01 340.3 2.65 8.91 0.24 0.2 99.5 1.59
F6 4.70 0.01 340.6 3.44 8.91 0.15 0.3 94.9 2.24
F7 4.69 0.02 339.6 2.33 9.03 0.32 0.4 97.03 1.81
The tablets of 7 formulations were tested and analysed for thickness, weigh variation, hardness,
friability, content uniformity.

Table No: 22 Cumulative % of drug release
Simulated intestinal fluid without Pancreatin, pH 7.5
Time(hr) Reference F1 F2 F3 F4 F5 F6 F7
1 0 100 00.58 00.90 00.71 00.85 01.27 01.12
2 3Product ** 00.50 00.67 00.82 31.08 150.9 191.37

3
4 19 ** 60.87 121.1 131.70 191.48 291.6 321.90
5
6 38 ** 120.99 221.08 251.75 362.70 481.5 621.97
9
8 55 ** 360.95 431.29 461.54 552.70 681.6 802
0
16 106 ** 811.31 820.57 850.57 1061.23 981.5 1030.30
9
f2 38 44 48 94 50 39
Fig. 11 Comparitive graph of all formulations with Innovator

6.4 DRUG RELEASE KINETICS MODEL:
Table No. 23 Drug Release kinetics model:
Formulation Zero First Higuchi KorsmeyerPeppas

order order model
R2 value N value
F1 0.954 -9.93 0.737 -0.83 -0.372
Model
F2 0.954
release -18.9
release 0.728 -0.41 -0.444
Code
F3 0.985 0.967 0.950
R2 value 0.130 0.575
F4 0.958 0.926 0.965 0.171 0.582
F5 R2 value
0.973 R2 value
0.847 0.971 0.961 1.836
F6 0.975 0.977 0.962 0.152 0.631
F7 0.932 -0.151 0.963 0.194 0.516
The drug release studies were analyzed for kinetics model to determine its order and mechanism of
drug release. The above table shows the data of formulations F1 to F7. From that all formulations F5
formulation is optimized based on the similarity factor. Figure no show the graphical representation
of order of kinetics of the optimized formulation.

Fig. 12 zero order release
Fig. 13 First order release

Fig. 14 Higuchi model
Fig. 15 KorsmeyerPeppas model

DISCUSSION
6.5 PHYSICAL CHARACTERISTICS OF GLIPIZIDE:
1. Solubility: The solubility is higher in pH 7.5 PBS. It is (0.250mg/ml).
2. Melting Point: Melting point of Glipizide was determined by capillary tube method and it was
found to be 208.5C (n = 3). This value is same as that of the literature citation.
6.6 CALIBRATION CURVES OF GLIPIZIDE IN DIFFERENT MEDIA:
Standard Calibration curves of Glipizide in different media were plotted by tacking concentration
ranging from 2 to 12g/ml.
Standard calibration curve of Glipizide in PBS pH 7.5: The slope area value was found to be
0.0526 and the coefficient of correlation (r) was found to be 0.999. From the slope area and intercept
values it was found that the curve is having a positive slope and intercept. As the coefficient of
correlation value is 0.999 the values are acceptable.
6.7 FT-IR RESULTS:
FT-IR studies were carried out for pure drug alone and along with excipients. The pure drug FT-IR
spectrum -c=o, urea stretching wavenumber 1653 cm-1, Cyclohexyl stretching wavenumber 1157
cm-1, SO2NH stretching wavenumber 1331 cm CONH stretching wavenumber 1637 cm-1 observed.
Similarly FT-IR spectra of glipizide in combination with excipients are shown in Figures no9 to 10.
The peaks can be considered as characteristic peaks of glipizide. These peaks were not affected and
prominently observed in FT-IR spectra. This indicates that there is no interaction between glipizide
and excipients and the drug was compatible with the formulation components.
6.8 FLOW PROPERTIES OF POWDERED BLEND:
Push layer powder blend is having good flow properties, for this layer no need of granulation. The
flow properties values are mentioned below.
Bulk density: The bulk density for the entire tablet blends lies within the range of 0.388 to
0.431gm/cm3.
Tapped density: The tapped density for the entire tablet blends lies within the range of 0.431 to
0.470gm/cm3.
Carrs Index: The percentage compressibility or Carrs index for the entire tablet blends lies within
the range of 3.4% to 13.3%. This indicates that all the formulations had shown good in flow
properties.
Hausners ratio: The Hausners ratio for the entire tablet blends lies within the range of 1.03 to
1.153. This indicates that all the formulations had shown good in flow properties.
Angle of Repose: The angle of repose for the entire tablet blends lies within the range of 21to 26.0.
This indicates that all the formulations had shown excellent in flow properties.
6.9 EVALUATIONS OF ANTI-DIABETIC CONTROLLED POROSITY
OSMOTIC TABLETS:
Prepared tablets of Glipizide of all the formulations (F1 to F7) were round in shape with convex
surfaces. All the formulations were evaluated for thickness, drug content, weight variation, hardness
and friability.
Tablet appearance:
All the formulated Anti-diabetic osmatic tablets were evaluated for their appearance . The tablets had
white to cream white in colour.
Drug content:
All the formulated Anti-diabetic osmotic tablets were evaluated for their drug content and the results
had shown in table-20. The drug content of all the formulations was in the range 94.132.00% to
102.51.99%sec. These results suggested the drug content had found out within the limits i.e,
( 90.0% to 110.0%) according to USP.
Tablet thickness:
Tablets thickness is one of the important physical parameter as it may affect the uniformity and pose
different in packing and also affect the hardness of the tablet. All the formulated Bilayer push pull
Anti-diabetic osmatic tablets were evaluated for their thickness and the results had shown in table
no-20. The thickness of all the formulations was in the range of 4.64 0.12 to 4.71 0.04.
Tablet Weight variation:
Tablet weight variation is one of the important parameter as it may affect the content uniformity of
the tablet. All the formulated Anti-diabetic osmatic tablets were evaluated for their weight variation
and the results had shown in table no-20. The weight variation of all the formulations was in the
range of 195.6 2.33 to 210.7 3.73. The weight variation of the tablets was within the permissible
limit of 5.0%, as USP specified for tablet weight more than 206mg.

Tablet Hardness:
Tablet hardness is one of the important parameter as it may affect the friability and disintegration of
the tablet. All the formulated Anti-diabetic osmatic tablets were evaluated for their hardness and the
results had shown in table no.20. The hardness of all the formulations was in the range of 6 0.25
kp/cm2 to 8 0.23 kp/cm2, which was found to be acceptable.
Tablet Friability:
Tablet friability is one of the important parameter to evaluate the ability of the tablets to withstand
abrasion in packing, handling and transporting. All th formulated Anti-diabetic osmatic tablets were
evaluated for their friability and the results had shown in table no-20. The friability of all the
formulations was in the range of 0.1% to 0.5%, which was found to be within acceptable limit of
<1% as USP specified.
6.10 In-Vitro DISSOLUTION STUDY:
In-vitro dissolution studies were conducted for a period of 16 hours using USP dissolution apparatus
II (ELECTROLAB, Mumbai) at rpm of 50 and at a temperature of 37 0.50c and 900ml dissolution
medium of 7.5PBS.
The in vitro drug release of F2 formulation with 3% osmogent and coating ratio 70:30 was found to
be 38%
F3 formulation with 3% osmogent and coating ratio 50:50 was found to be 44%
F4 formulation with 5% osmogent and coating ratio 70:30 was found to be 48%
F5 formulation with 5% osmogent and coating ratio of 50:50 was found to be 94%.
F5 was found to be optimized formula as the concentration of osmogent (NaCl) increases,drug
release also increases and also as the concentration of pore former (PEG) increases, the number
of pores formed increases and drug release also increases.
In F5 formulation, there is increase in both pore former and osmogent.
Finally 3% coating buildup 5% sodium chloride and 50:50 ratio of cellulose acetate :polyethylene
glycol containing formulation F12 had maximum cumulative % Drug release was found to be 94%.

6.11 COMPARISON OF DISSOLUTION PROFILE:

The In-vitro drug release profile of the all formulations (F1 to F7) were compared with innovator
product i.e., Glucotrol XL In-vitro drug release profile. The similarity factor of all formulations
ranged from 38% to 94%. From all formulations, the F5 formulation has highest similarity factor
value that is found to be 94%, then F6formulation has second highest value is 50% and F2
formulation has lowest similarity factor value that is 38%.
6.12 INFLUENCE OF TABLETS FORMULATION VARIABLES ON
GLIPIZIDE RELEASE RATE:
Influence of sodium chloride amount on drug release rate: To study the influence of NaCl
amount on Glipizide release rate, showed that release rate increased significantly as the increase of
Nacl amount from 30mg to 70mg.
6.13 DRUG RELEASE KINETICS MODEL:
The drug release studies were analyzed for kinetics model to determine its order and mechanism of
drug release. Table No 23 shows the data of formulations F1 to F7 Drug Release kinetics values. The
n values for all the formulations ranged from 0.418 to 1.836 indicating different release patterns viz.
Fickian (n = 0.5), case II non-Fickian (anomalous) release (0.5 n 0.89), super case II type of
release (0.89). Based on the diffusion control studies, it was observed that the optimized
formulation F5 it follows zero order release (0.973), endured super case II release mechanism (n=
1.836), during the dissolution study, which indicated that polymer relaxation had a significant role in
the drug release mechanism. In the non-Fickian (anomalous) case II release, the rate of drug release
is due to the combined effect of drug diffusion and polymer relaxation. Super Case II release
generally refers to the polymer relaxation. Nature of release of the drug from the osmatic tablets was
inferred based on the correlation coefficients obtained from the plots of the kinetic model.

6.14 DRUG CONTENT STABILITY DATA :

Table.No:24 Drug content data of stability formulation F5
Sl. 1st 30th 60th

No.
Trial No. 90th day (%)
1. I 99.89 98.41 98.29 97.30
2. II 99.12 98.85 98.40 97.44
3. III 99.23 98.47 98.10 97.63
4. Mean ( X ) 99.56 98.92 98.60 97.94
S.D 0.67 0.68 0.70 0.84

5.
The stability studies were conducted for the optimised fomulation F5 for 3 months The stability
studies results concluded that the drug content deviation is with in the limits after 3 months duration
also.
6.16. STABILTY OF OPTIMISED FORMULATION F5:
Table.No.25: In vitro drug release data of the stability formulation F5
Sl. Cumulative* % drug released* S.D at 40 1 C

No. Time (h)
1st day 30th day 60th day 90th day
1 1 0 0 0 0
2. 2 3 2.9 2.8 2.8
3. 4 79.8 78.79 78.14 77.69
4. 6 86.27 86.12 85.88 85.12
5. 16 106 105.43 104.25 103.87

SUMMARY AND CONCLUSION
SUMMARY
The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in
the body and also to promptly achieve and maintain the desired drug concentration over entire period
of treatment.
Osmosis is one of the widely used methods for developing the new oral dosage forms to
control the drug release from the dosage form, improve the bioavailability, reduce adverse
effects especially drug with small therapeutic range and prolong the action of drug.
Glipizide is a potent antidiabetic agent used in the treatment of diabetes. It is insoluble in
water and ethanol, soluble in chloroform. The plasma half-life of glipizide is 1.5- 2 hours, has
short elimination half life of 2-3 hours.
In the present study seven formulations were formulated by using various concentrations of
sodium chloride and varying coating percentages of cellulose acetate and polyethylene glycol
400.
In-vitro study of formulations F2 , F3 and F4 showed slow release of drug. F6 and F7 had
shown faster drug release rate. F5 showed good controlled release profile.
F5 formulation with 1:5 (drug :osmogent ratio) and 50:50 (cellulose acetate : Polyethylene
glycol 400) was finalized as optimized formula
In-vitro release profile of formulation F5 was found to be similar to that of marketed
innovator product (Glucotrol XL).The f2values for the comparison of release of drug from
the formulation F4 with the marketed innovator product drug release profile were found to be
94%. Finally the F5 formulation was optimized.

SUMMARY AND CONCLUSION
CONCLUSION
The conclusions drawn from the present investigation are as follows.
Extended release formulations of Glipizide were developed based on controlled porosity
osmotic pump technology.
Core tablets of Glipizide were successfully prepared by wet granulation for drug layer using
Glipizide, sodium chloride,polyox WSR Cogulant , Magnesium stearate and ethanol used as a
granulating fluid. After compression core tablets coated with cellulose acetate as a
semipermiable membrane, PEG 400 as a plasticizer, acetone and water used as a solvents.
In vitro release profile of formulation F5 was found to be similar to that of marketed
innovator product (Glucotrol XL).The f2values for the comparison of release of drug from
the formulation F4 with the marketed innovator product drug release profile were found to be
94%. Finally the F5 formulation was optimized.
The effect of different formulation variable was studied to optimize release profile. The
release rate increased significantly as the increase of sodium chloride amount from 30mg to
70mg.

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DESIGN AND FORMULATION OF CONTROLLED POROSITY

OSMOTIC PUMP BASED DRUG RELEASE OF GLIPIZIDE

in partial fulfillment of the requirement for the award of the degree of

Under the guidance of

Department of Industrial Pharmacy

DECLARATION BY THE CANDIDATE

I KATTAMURI THULASI BHAVANI, of II year M. Pharmacy bearing Regd. No

FORMULATION OF CONTROLLED POROSITY OSMOTIC PUMP BASED

DRUG RELEASE OF GLIPIZIDE was carried out by me under the guidance of

Mr. Raghavendra Kumar Gunda (College Guide) Mr. K.Rambabu (Industrial

or in full for any degree or diploma of this or other university.

Date: Name and Signature of the Student

At this moment of accomplishment, I am extremely indebted to my guide Mr.

My Sincere thanks to Dr. Chandan Kumar Brahma M.pharm., Ph.D Department

I am also very much thankful to Mr. K. Nagaraju, Librarian of Narasaraopeta

KATTAMURI THULASI BHAVANI

S.NO CHAPTER PAGE NO.

2. AIM& OBJECTIVE 18-19

4. LITERATURE SURVEY 21-24

5. MATERIALS AND METHODS 25-47

6. RESULTS AND DISCUSSION 48-61

7. SUMMARY AND CONCLUSION 62-63

S.No Title Page No.

2 Working principle of osmosis 6

4 Drug release mechanism of osmotic pump tablets 11

S.NO TITLE PAGE NO

FT IR Fourier Transformer Infrared Spectroscopy

Hcl Hydrochloric acid

HPMC Hydroxy propyl methyl cellulose

GIT Gastrointestinal tract

CRDDS Controlled Release Drug Delivery System

BCS Biopharmaceutical Classification System

AUC Area Under the Curve

Ph Eur European Pharmacopoeia

USP United States Pharmacopoeia

PVP Polyvinyl pyrolidone

IPA Isopropyl alcohol

Frequency reduction in dosing Extended release products deliver frequently more

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 1

Enhanced patients With less frequency of dose administration, a

Reduction in overall health Although the initial cost of extended-release

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 2

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 3

2. Delayed Release Dosage Forms:

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 4

a. Dissolution controlled release system

ii) Matrix devices

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 5

Fig.2 Working principle of osmosis

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 6

Table No: 2 Osmotic pressures of saturated solutions of commonly used

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 7

(a) The Rose and Nelson Pump.

Delayed Delivery Osmotic device,

Fig.3 Three chamber rose nelson pump

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 9

Table No: 3. Single Chamber Osmotic Pumps

Osmotic Design of Mechanism Application Figure

Table No: 4. Multi Chamber Osmotic Pumps

Push pull Core tablet: 2 After coming in This method is

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 10

Sandwiched Core tablet: 3 The middle push API release

Fig. 4 Drug release mechanism of controlled porosity osmotic pump.

DEPATRMENT OF INDUSTRIAL PHARMACY, NIPS Page 11