Design and Development of Once A Day Ora

Design and Development of Once a Day Oral Osmotic
Drug Delivery System of Ropinirole

By
Pansuriya Purvang C.
Dissertation submitted to the

KLE Academy of Higher Education and Research-Deemed University, Belgaum
Karnataka
In partial fulfilment of the requirement for the degree of
Master of Pharmacy
in
Pharmaceutical Technology
Under the guidance of
Mrs. Uma A. Patil
Department of Pharmaceutical Technology,

KLE University’s College of Pharmacy,
Bangalore-560010
2011
KLE Academy of Higher Education and Research –
Deemed University, Belgaum
Karnataka
DECLARATION BY THE CANDIDATE

I hereby declare that the dissertation entitled
“Design and development of Once A Day Oral Osmotic Drug

Delivery system Of Ropinirole”
is a bonafide and genuine research work carried out by me under the guidance of
Mrs. Uma A. Patil, Asst. Professor, KLE University’s College of
Pharmacy, Rajajinagar, Bangalore.
Date:
Place: Bangalore Pansuriya Purvang C.
Bangalore-560010
(A constituent unit of KLE Academy of Higher Education and Research

– Deemed University)
CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled

is a bonafide and genuine research work carried out by Pansuriya Purvang C.
in partial fulfilment of the requirements for the degree of Master of
Pharmaceutical Technology.
Date: Mrs. Uma A. Patil

Asst. Professor
Place: Bangalore Department of Pharmaceutical Technology
Bangalore-560010
Bangalore-560010
(A constituent unit of KLE Academy of Higher Education and Research

– Deemed University)
ENDORSEMENT BY THE HEAD OF THE DEPARTMENT AND

THE PRINCIPAL/HEAD OF THE INSTITUTION
This is to certify that the dissertation entitled

is a bonafide and genuine research work carried out by Pansuriya Purvang C.
under the guidance of Mrs. Uma A. Patil, Asst. Professor, KLE
University’s College of Pharmacy, Bangalore.
Date: Dr. B. G.
Dr.Desai
B. G. Desai
Principal and H.O.D.
Principal and H.O.D.
Place: Bangalore Dept. of Pharmaceutical Technology
Dept. of Pharmaceutical Technology
KLE University’s College of Pharmacy
KLE University’s College of Pharmacy
Bangalore-560010
Bangalore-560010
COPYRIGHT
DECLARATION BY THE CANDIDATE
I hereby declare that the KLE Academy of Higher Education and
Research – Deemed University have the rights to preserve, use and
disseminate this dissertation/thesis in print or electronic format for
academic / research purpose.
Date:
Place: Bangalore Pansuriya Purvang C.
© KLE Academy of Higher Education and Research-Deemed University
I
Acknowledgements
Acknowledgements
Research work. The name only reflects its immensity. It would be delinquent
on my part if I don’t convey my heartfelt gratitude to “THEM”. I have intentionally
put that word in uppercase because, in their absence this work would have been left
out crude.
Life is a chemistry, just dilute your sorrows,
evaporate your worries, filter ur mistake,
boil your ego and you will get the crystal of
happiness.
Starting with The creator. I know that my words are not enough to greet Him.
I am thankful to the Almighty for keeping me in a pleasant state of mind and good
health throughout my task.
Amour! Without their love and support I would have been a vagabond.
Keeping my parents second in the list doesn’t mean that they are in any
circumstances lesser than the God. I am grateful to them and I don’t require any
reason for it.
My guide. My philosopher. It is just for the sake of differentiating that I

consider her after my mother. I deliver a blossoming flower to Mrs. Uma A. Patil.
She is one of kind. She, without her knowledge, gave me the most precious gift. With
her serenity, she taught me to control my temperament. With her confounding
support and care it was possible for me to complete my work.
How could I forget to show my poignant gratification to Dr. Rajeshri Dhurke

and Dr. Bijiya Ghosh, as they silently in the backdrop were shaping my task!
Nitin Dobariya. My brother. He was as disquiet as me and finally provided me

with the drug. I am also very indebted to Colorcon and sunrise remedies for giving
away the polymers.
DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY, KLEUCP, BANGLORE. 1

Acknowledgements
Whenever it comes to pen down the names I want to acknowledge, I would

never forget Dr. Purnima Ashok, Dr. S.S.Karki, Dr. Sonal Dubey, Mrs. Vanitha S.,
Mr. Y.D.Satyanarayana, Mr. Sujit, Mr. Satish (Librarian) and other faculty members
and the non-teaching staff Mr. Biradar, Mr. Prakash, Mr. Chandrashekhar, Mr. Jatti,
Mr. Patil, Ms. Prema, Mr. Ramachandra, Mr. Suresh, Mrs. Vibha of KLE Society’s
College of Pharmacy, Bangalore for their small yet useful help.
Friend is a medicine for any kind of wound
But
There is no medicine found in the world for would given by
Friend.............!
Lastly my contemporaries and junos in the snap and its picture perfect. My
heart-rending gratitude to Dhaval, Bhuppender, Rikin, Amit, Chirag, Irisha, Kathan,
Rakesh, and Sandip. They made this taxing work simple.
Date:-
Place:- Bangalore Pansuriya Purvangkumar C.

TABLE OF CONTENTS
Sr. No. Contents Page No.
1. Introduction 1
2. Objective 21
3. Review of Literature 22
4. Methodology 50
5. Results 65
6. Discussion 98
7. Conclusion 101
8. Summary 102
9. Bibliography 104
LIST OF ABBREVIATION
 % CR: Percentage cumulative release
 API: Active pharmaceutical ingredients

 CA: Cellulose acetate
 COMT: Catechol-o-methyl transferase
 CPOP: Controlled porosity osmotic pump
 CPOP: Controlled porosity osmotic pump

 DL : Loading dose
 DM : Maintenance dose
 DSC: Differential Scanning Calorimetry
 EOP: Elementary osmotic pump
 FTIR: Fourier Transform Infrared
 HCl: Hydrochloric acid
 HPMC: Hydroxy propyl methyl cellulose
 IVIVC: In vivo- in vitro correlation
 JP: Japanese Pharmacopoeia
 KCl: Potassium chloride
 L-dopa: Levodopa
 L-OROS: Liquid oral release osmotic system
 MCC: Microcrystalline cellulose

 Mg.Sterate: Magnesium Stearate
V
 Mg: Milligram
 MOB: Monoamine oxidase
 NaCl: Sodium chloride
 OROS-CT : Oral release osmotic system colon targeting
 PD: Parkinson disease
 PEG: Polyethylene glycol
 PEO: Poly ethylene oxide
 Ph Eur: Pharmacopoeia of Europe
 PVP: Poly vinyl pyrrolidone
 R: Regression coefficient
 SD: Standard deviation
 SLS: sodium lauryl sulphate
 SOTS: Sandwiched osmotic tablets
 USP: United State Pharmacopoeia
 USPNF: United State Pharmacopoeia National Formulary
 UV: Ultraviolet
V
Abstract
ABSTRACT
Ropinirole is a nonergoline dopamine D2-receptor agonist that has been

proven to be effective in both monotherapy and combination therapy for idiopathic
Parkinson’s disease. In advanced parkinson’s disease the usual dose of ropinirole is
1to 2 mg three times a day.
Hence the objective of the research work was to design and develop once a
daily oral osmotic tablet that can deliver ropinirole for prolonged period of time.
Core of osmotic tablet was prepared by blending drug, osmotic agents and
hydrophilic polymer which was then coated with controlled porosity osmotic
membrane. The membrane was formed by using cellulose acetate with water
soluble pore forming agents which released drug through pores formed after
imbibing water. In-vitro release studies were carried out at different rpm using
different dissolution media. The rate of drug release was found to be independent
of dissolution media and agitation rates. However, the nature of osmogents was
found to significantly influence the release of the drug. The studies also indicated
that dense coat with or without mechanical drill was not as efficient as controlled
porosity membrane in controlling the release. The data obtained from release
profiles was fitted with different kinetic models to determine the release pattern.
The optimized formulation showed high regression values of 0.9825 for zero order
release pattern and 0.7955 and 0.9477 for Higuchi and Korsmeyer’s equation
respectively. From the regression values it was confirmed that drug was released by
zero order and not by diffusion. The release rate was increased with increase in
concentration of osmotic agent and was found to be linear with osmotic pressure.
Key words: Ropinirole, Parkinson’s disease, osmotic tablet, controlled porosity

osmotic membrane.
INTRODUCTION
1. INTRODUCTION
1.1: Oral controlled drug delivery system:
Oral drug delivery is the largest and the oldest segment of the total drug
delivery market. It is the fastest growing and most preferred route for drug
administration. Conventional oral drug delivery system delivers the drug
immediately. Hence in order to maintain the plasma drug concentration in a
therapeutic effective range, it is needful to administer the dosage form several times
a day. This leads to fluctuations in the plasma concentration of the drug as well as
precipitation of side effects. So, in order to minimise the problems following the
conventional drug delivery system, it is essential to fabricate the drug into a
controlled release system. In the recent years, pharmaceutical research has led to
the development of several novel drug delivery systems like oral, mucosal, nasal,
ocular, parenteral, intra-uterine, vaginal drug delivery system etc. Oral controlled
release system continues to be the most popular and most widely used amongst all
the drug delivery systems, because pharmaceutical agents can be delivered in a
controlled pattern over a long period increasing therapeutic value of the drug. Oral
controlled release formulations are becoming increasingly popular in the
pharmaceutical industry because they improve likelihood that a patient will actually
take the medicine, reduce the side effects and provide an extended patient
protection.
Oral controlled drug delivery system can be classified as rate programmed

drug delivery system and stimuli-activated drug delivery system.
1. Rate programmed drug delivery system: In this drug delivery system, the
drug release has been programmed at specific rate profile.
 Dissolution controlled drug delivery system.
i. Slow dissolution rate of the drug,
ii. Slow dissolution rate of the reservoir membrane or matrix.
 Diffusion controlled drug delivery system.
i. Porous matrix controlled system,
ii. Porous membrane controlled system.

INTRODUCTION
 Erosion controlled drug delivery system.

i. Surface erosion,
ii. Bulk erosion.
 Combination of dissolution, diffusion and/or erosion controlled drug
delivery system.
i. Reservoir system,
ii. Matrix system,
iii. Hybrid system.
2. Stimuli-activated drug delivery system: In this drug delivery system, the

drug release is activated by some stimuli like biological, chemical and
physical energy supplied externally.
 Activation by the biological process:
 Enzyme activated drug delivery system.
i. Urea responsive drug delivery system,
ii. Glucose responsive drug delivery system.
 Antibody interaction activated drug delivery system.
 Antigen activated drug delivery system.
 Inflammation activated drug delivery system.
 Activation by the chemical process:

 pH activated drug delivery system.
i. pH dependent solubility system,
ii. pH dependent erosion/degradation system,
iii. pH dependent swelling system.
 Ion activated drug delivery system.
 Hydrolysis activated drug delivery system.
 Chelation activated drug delivery system.

INTRODUCTION
 Activation by the physical process:

 Electrically activated drug delivery system.
i. Iontophoresis,
ii. Electroporation
 Hydrodynamic pressure activated drug delivery system.
 Mechanical forced activated drug delivery system.
 Magnetically activated drug delivery system.
 Photo activated drug delivery system.
 Photomechanical waves (Laser) activated drug delivery system.
 Phonophoresis/sonophoresis/ultrasound activated drug delivery system.
 Thermally activated / Temperature responsive drug delivery system.
 Osmotic pressure activated drug delivery system.
Many drug delivery systems have been devised by researchers to modulate

and release a drug over an extended period of time. The majority of these systems
are matrix-based and their principle drug- release mechanism is based on drug
diffusion through matrix system. However, this diffusion is altered by the pH of the
medium, the presence of food, and the body’s physiological factors, all of which can
cause difficulty in controlling the drug release rate.
Another delivery method used is the osmotic drug release system, where the
release rate is unaffected by the body’s pH, presence of food, and the body’s
physiological factors. There has been increasing interest in the development of
osmotic devices over the past 3 decades.
1.2: Osmotic drug delivery system:
Oral osmotic drug delivery system is also known as gastro-intestinal

therapeutic system. Development of osmotic drug delivery system was pioneered by
ALZA. This system was first used by Australian scientists ROSE and NELSON in
1955.

INTRODUCTION
The release of drug from osmotic system is governed by various formulation

factors such as solubility, osmotic pressure of core components, size of the delivery
orifice and nature of the rate-controlling membrane. Osmotic pressure is used as
driving force in drug delivery system as a mechanism to release the drug is in
controlled manner at zero order rates, independent of pH and environmental factor.
1.2.1: Osmosis:
Osmosis can be defined as the net movement of water or solvent driven

by a difference in an osmotic pressure from lower concentration of solute
towards higher concentration of solute across a semipermeable membrane
that allows passage of water or solvent, but reject solute molecules or ions.
1.2.2: Osmotic pressure:
Osmotic pressure is a pressure developed when two solutions at

different concentrations are separated by a semipermeable membrane.
1.2.3: Principle of osmotic drug delivery system:
This type of activation controlled drug delivery system depends on

osmotic pressure to activate the release of a drug. This system contains the
drug along with osmotic agent (osmogen) coated by semipermeable
membrane, made from biocompatible polymer, e.g. - cellulose acetate.
That is permeable only to water but not to drug. The drug is activated to
release in solution form at a constant rate through a special delivery orifice.

INTRODUCTION
1.2.4: Advantages:
 They are well characterized and understood.

 The release mechanisms are not dependent on drug.
 Reformulation for different drug is not required.
 Release of drug is independent of the environmental system, pH etc.
 Zero order release profile could be achieved.
 The drug is released in solution form which is ready for adsorption.
 In vivo- in vitro correlation (IVIVC) is possible in osmotic system.
 The release of drug from osmotic system is minimally affected by the
presence of food.
 Improves the patient compliance because of reduced dosing frequency.
1.2.5: Disadvantages:
 If the coating process is not well controlled, then there could be a risk
of film defects, which results in dose dumping.
 Orifice size is critical.
 More expensive than the conventional drug delivery system.
 Quality control tests are more extensive than most of the conventional
tablets.
1.2.6: Applications:
 Acutrim tablets working on the principle of osmotic drug delivery

containing phenylpropanolamine HCl is used as nasal decongestant.
 Alzet osmotic pump is used as implantable drug delivery.
 Principle of osmotic drug delivery is also applied to pulsatile delivery of
the drug. It works on the principle of chronotherapeutics.
 Osmotic drug delivery system is used in pharmacological studies,
Implantation therapies and oral drug delivery.

INTRODUCTION
1.2.7: Different types of osmotic system:
Osmotic drug delivery system can be classified in to three types given below:
 Single chamber osmotic system

Ex.:- Elementary osmotic pump, Controlled porosity osmotic pump,
Osmotic bursting osmotic pump.
 Multi chamber osmotic system
Ex.:- Push-pull osmotic pump, Sandwiched oral therapeutic system.
 Miscellaneous
Ex.:- Lipid osmotic pump, multi particulate osmotic pump, Liquid oral
release osmotic system, Delayed delivery osmotic device, Telescopic
capsule for delayed release, Oral release osmotic system colon targeting,
Osmotic pump for insoluble drugs, Osmat, Monolithic osmotic system, etc.
 Single chamber osmotic system:

1. Elementary osmotic pump (EOP).
Core: API + Osmogents.
Coat: Semi permeable membrane with delivery orifice.
Mechanism: The water penetrates inside the dosage form at the rate
determined by the fluid permeability of the membrane and osmotic pressure
of core formulation. This results in formation of saturated solution of drug
within the core, which is dispensed at a controlled rate from the delivery
orifice in the membrane.
2. Controlled porosity osmotic pump (CPOP).

Core: API + Osmogents.
Coat: Semi permeable membrane with water soluble additives.
Mechanism: Water-soluble additives dissolve after coming in contact with
water, resulting in an in situ formation of a microporous membrane. The
resulting membrane is substantially permeable to both water and dissolved
solutes and the drug release is controlled by osmotic pressure.

INTRODUCTION
3. Osmotic bursting osmotic pump.
Core: API + Osmogents
Coat: Semi permeable membrane without delivery orifice
Mechanism: When placed in an aqueous environment, the imbibed water

built up hydraulic pressure inside the system causing the rupturing of the
wall and eventually releasing the contents.
 Multi chamber osmotic system:
1. Push-pull osmotic pump.

Core Tablet: Layer 1: API + Osmogents,
Layer 2: Polymeric osmotic agent.
Coat: Semi permeable membrane with delivery orifice.
Mechanism: After coming in contact with the aqueous environment,
polymeric osmotic layer swells and pushes the drug layer, thus releasing the
drug in the form of fine dispersion via the orifice.
2. Sandwiched osmotic tablets (SOTS).
Core tablet: 3 layers,
2 attached layers: API, Middle layer: push layer (Swellable Polymer).
Coat: Semi permeable membrane with two side delivery orifice.
Mechanism: The middle push layer swells and drug is released from
delivery orifices.

INTRODUCTION
 Miscellaneous
1. Liquid oral release osmotic system (L-OROS) soft and hard capsule.
Design of dosage form: Liquid API formulation is present in a soft gelatin

capsule, which is surrounded with the barrier layer, the osmotic layer, and
the release rate-controlling membrane. A delivery orifice is formed through
these three layers.
Mechanism: When the system comes in contact with aqueous environment,

water permeates across the rate controlling membrane and activates the
osmotic layer. The expansion of the osmotic layer results in the development
of hydrostatic pressure inside the system, thereby forcing the liquid
formulation to break through the hydrated gelatin capsule shell at the
delivery orifice.
2. Oral release osmotic system colon targeting (OROS-CT).
Design of dosage form: Enteric coated single osmotic unit or a unit

containing as many as five to six push pull osmotic pump filled in hard
gelatin capsule.
Mechanism: Gelatin capsule shell dissolves after coming in contact with GI

fluids. Enteric coating on the system prevents entry of fluid from stomach to
the system and it dissolves after entering into intestine. The water imbibes
into the core and push compartment swells. At the same time, the flowable
gel is formed which is pushed out via delivery orifice at predetermined rate.
3. Multi-particulate osmotic pump.
Design of dosage form: Multi-particulate delayed release systems consist of

pellets of API with or without osmogents coated with semipermeable
membrane.
Mechanism: Rapid expansion of membrane after coming in contact with

aqueous environment resulting in pore-formation and API release.

INTRODUCTION
4. Telescopic capsule for delayed release.
Design of dosage form: This device consists of two chambers, the first
contains the drug and an exit port, and the second contains osmotic engine.
Layer of wax-like material separates the two sections.
Mechanism: As the fluid imbibes the housing of the dispensing device, the
osmotic engine expands and exerts pressure on the slidable connecting the
first and second wall sections.
5. Osmotic pump for water insoluble drug:
Design of dosage form: Capsule wall made up of water insoluble

semipermeable polymer.
Mechanism: Imbibition of water through the capsule wall and dissolving

soluble components within it and releasing from same wall.
6. Osmat:
It is a novel osmotically driven matrix system, which utilizes the
hydrophilic polymers to swell, and gel in aqueous medium forming a
semipermeable membrane in situ. Drug release from such a matrix system
containing an osmogen could, therefore be modulated by the osmotic
phenomenon. Osmat thus judiciously combines both matrix and osmotic
characteristics resulting in a quantum improvement in drug delivery from
swellable matrix system.
Osmat represents simple, versatile, and easy to fabricate osmotically
driven controlled drug delivery system based upon low cost technology.
7. Monolithic Osmotic System:
It constitutes of a simple dispersion of water-soluble agent in a

polymeric matrix. When the system comes in the contact with an aqueous
environment, water imbibes through the semipermeable membrane and
comes in contact the with osmogen. This osmogen dissolves and creates an

INTRODUCTION
osmotic pressure and the drug in a solution form continuously comes out
through the pores or delivery portal.
1.2.8: Factors affecting drug release rate:
1. Solubility: - APIs for osmotic delivery should have water solubility in the
desired range to get optimized drug release. However, by modulating the
solubility of these drugs within the core, effective release patterns may be
obtained for the drugs, which might otherwise appear to be poor candidate
for osmotic delivery.
Solubility-modifying approaches:
 Use of swellable polymers like vinyl acetate copolymer, polyethylene oxide

etc.
 Use of effervescent mixtures.
 Use of cyclodextrin derivatives: which are known to increase solubility of
poorly soluble drugs.
 Use of encapsulated excipients: Solubility modifier excipient used in form of
mini-tablet coated with rate controlling membrane.
 Resin modulation using Ion-exchange resin like Pentaerythritol, citric acid,
adipic acid etc.
 Co-compression of drug with organic acids, buffering agent, etc.
 Use of crystal habit modifiers which may change crystal habit of the drug
and used to modulate solubility.
2. Osmotic pressure: The next release-controlling factor that must be

optimized is the osmotic pressure gradient between inside the compartment
and the external environment. The simplest and most predictable way to
achieve a constant osmotic pressure is to maintain a saturated solution
of osmotic agent in the compartment.
3. Size of delivery orifice: To achieve an optimal zero order delivery profile,

the cross sectional area of the orifice must be smaller enough to minimize
drug delivery by diffusion through the orifice. Furthermore, the area must be

INTRODUCTION
sufficiently large, to minimize hydrostatic pressure build up in the system.

The typical orifice size in osmotic pumps ranges from 600µ to 1 mm.
Delivery orifices can be formed in the osmotic tablet by:
 Mechanical drill
 Laser drill: This technology is well established for producing sub-millimeter
size hole in tablets.
 Indentation is made in core tablets by using modified punches having needle
on upper punch. This indentation is not covered during coating process
which acts as a path for drug release in osmotic system.
 Use of leachable substances in the semipermeable coating: e.g. controlled
porosity osmotic pump.
1.2.9: Basic components of osmotic system:
1. Drug: - Drug which have short biological half-life and which is used for
prolonged treatment are ideal candidates for osmotic drug delivery system.
Ex.:- Ropinirole, tramadol, repaglinide, oxybutynin, pramipexole,

chlorpheniramine, phenylpropanolamine, isradipine, etc.
2. Polymer: - Polymers are used to formulate a matrix core of the drug. The
highly water soluble compounds can be co-entrapped in hydrophobic
matrices and moderately water soluble compounds can be co-entrapped in
hydrophilic matrices to obtain more controlled release. The 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 drugs as well as the amount and rate of drug to be released from
the pump.
The polymers can be either swellable or non-swellable in nature.

Swellable polymers are used for the moderately water soluble drugs and
non-swellable polymers are used in case of highly water soluble drugs.
Ex.:- Hydrophilic polymer such as Hydroxy propyl methyl cellulose,

Hydroxy ethyl cellulose, Carboxy methyl cellulose etc.

INTRODUCTION
Hydrophobic polymer such as ethyl cellulose and wax material etc.
3. Osmotic agents: - Osmotic agents are essential ingredients of osmotic

formulations. Osmotic agents are used to achieve optimum osmotic pressure
inside the system. The simplest and most predictable way to achieve
constant osmotic pressure is to maintain a saturated solution of osmotic
agents in the compartment. Inorganic salts and carbohydrates are used as
osmotic agent. Combinations of osmotic agents are also used to achieve
optimum osmotic pressure inside the system. Commonly used osmotic
agents are given below:
Table 1: Osmotic pressure of common pharmaceutical solutes
Osmotic agents Osmotic Pressure (atm)
Sodium chloride 356
Fructose 355
Potassium chloride 245
Sucrose 150
Dextrose 82
Potassium sulphate 39
Mannitol 38
Sodium potassium tri-basic 36
Sodium potassium di-basic 31
Sodium potassium monobasic 28
Lactose-fructose 500
Dextrose-fructose 450
Sucrose-fructose 430
Mannitol-fructose 415
Lactose-sucrose 250
Lactose-dextrose 225
Mannitol-dextrose 225
Dextrose-sucrose 190
Mannitol-sucrose 170
Mannitol-lactose 130

INTRODUCTION
4. Wicking agents: - Wicking agent is swellable or non-swellable in nature

and is used to carry water to surfaces inside the core of the tablet increasing
the surface area for drugs which have a low solubility in water, the wicking
agent aids in the delivery of partially solubilized drug through the
passageway in the semipermeable coating.
Ex.:- colloidal silicon dioxide, kaolin, titanium dioxide, alumina,

niacinamide, sodium lauryl sulphate (SLS), poly vinyl pyrrolidone (PVP),
bentonite, magnesium aluminium silicate, etc.
Sodium lauryl sulphate, colloidal silicon dioxide, and poly vinyl pyrrolidine
are non-swellable wicking agents.
5. Semi-permeable membrane: - An important part of the osmotic drug

delivery system is the semipermeable membrane housing. Therefore, the
polymeric membrane selection is a key to osmotic delivery formulation. The
membrane must possess certain performance criteria such as:
 Sufficient wet strength and water permeability,
 Should be biocompatible,
 Should be rigid and non-swelling,
 Should be sufficiently thick to withstand the pressure within the
device.
Any polymer that is permeable to water but impermeable to solute can be

used as a coating material in osmotic devices.
Ex.:- Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose
triacetate, ethyl cellulose and eudragits.
6. Coating solvents:- Coating solvents include inert organic and inorganic

solvents that do not adversely harm the core, wall and other material.
Ex.:- acetone, methanol, ethanol, isopropyl alcohol, butyl alcohol,

dichloromethane, ethyl acetate, cyclohexane, carbon tetrachloride, water,
etc.

INTRODUCTION
The mixture of solvents such as acetone-methanol (80:20), acetone-ethanol

(80:20), acetone-water (90:10), methylenechloride-methanol (79:21),
methylenechloride-methanol-water (75:22:3) etc.
7. Plasticizers: Plasticizer used in coating membrane has a significant

importance in the formulation of osmotic systems. They increase the
workability, flexibility, and permeability of the fluids. They can change
visco-elastic behaviour of polymers and these changes may affect the
permeability of the polymeric films. Some of the plasticizers used are as
below:-
 Polyethylene glycols
 Tri ethyl citrate
 Ethylene glycol monoacetate and Ethylene glycol diacetate – For
low permeability
 Diethyl tartarate or diacetin – For high permeability.
8. Pore forming agents: - Pore forming agents are used in the pumps
developed for poorly water-soluble drug. The pore-former should be non-
toxic and can be an organic or inorganic solid or liquid..
Ex.:- Alkaline metals such as sodium chloride, sodium bromide, potassium
chloride, potassium sulphate, potassium phosphate etc.
 Alkaline earth metals such as calcium chloride and calcium nitrate.
 Carbohydrate such as sucrose, glucose, fructose, mannose, lactose,
etc.
 Diols and Polyols such as poly hydric alcohols and poly vinyl
pyrrolidone.
These systems hold a major market share in the drug delivery products as
exemplified by the number of products in the market and patents granted in the last
few years.

INTRODUCTION
Table 2: Marketed products of Elementary osmotic pump
Marketed Active pharmaceutical Dose Class Use

name ingredients
Acutrim Phenylpropanolamine 75mg β-Adrenergic Nasal
agonist decongestant
Efidac24 Chlorpheniramine 4-12mg H1 Cough and
Antagonist cold
Minipress XL Prazocine 2.5-5mg α-Adrenergic Anti-
agonist hypertensive
Sudafed24 Pseudoephedrine 30-60mg β-Adrenergic Nasal
agonist decongestant
Table 3: Marketed products of Push pull osmotic system
Marketed Active Dose Class Use

name pharmaceutical
ingredients
Cavera HS Verapramil 180-240mg Calcium Anti-
channel hypertensive
blocker
Dynacric CR Isradipine 5-10mg Calcium Anti-
blocker
Glucotrol Glipizide 5-10mg Oral Anti-
hypoglycemic diabetic
Procardia XL Nifedipine 30-90mg Calcium Anti-

blocker

INTRODUCTION
1.2.10: Patents of osmotic drug delivery system:
Table 4: Patent of osmotic drug delivery system
Patent and Number Title Company

US-6283953 Osmotic drug delivery Alza corporation
monitoring system and
method.
US-4224048 Osmotic fertilizer product and Hector incorporated engle
fertilization method. wood cliff
European-20100112052 Osmotic tablet with a Johnson and Johnson
compressed outer coating.
European-20080299197 Triple combination release Osmotica corporation
multi-layer tablet.
1.3: Parkinson’s disease
Parkinson’s disease is a neurological disorder that affects movement, muscle

control, and balance. Parkinson’s disease usually affects people in the age group of
55 - 75 years but can also be developed in younger people. The disease is
progressive, with symptoms becoming more severe over time.
Parkinson's disease also known as Parkinson's, Parkinson disease or PD.

Parkinson's disease is a progressive, neurodegenerative disorder that affects
movement, muscle control, and balance as well as numerous other functions. It is
part of a group of conditions known as motor systems disorders. Parkinson's disease
was named after James Parkinson, a general practitioner in London during the 19th
century who first described the symptoms of the disease. Symptoms describing
Parkinson's disease are mentioned in the writings of medicine in India dating back
to 5,000 BC as well as in Chinese writings dating back approximately 2500 years.
Parkinson's disease is the most common movement disorder and the second most
common neurodegenerative disorder, after the Alzheimer's disease.

INTRODUCTION
The hallmark symptoms of Parkinson's disease (PD) are asymmetric tremors

at rest, rigidity, and bradykinesia (slowness in movement). There is currently no
cure for Parkinson's disease; it is always chronic and progressive, meaning that the
symptoms always exist and always worsen over time. The rate of progression varies
from person to person, as does the intensity of the symptoms. Parkinson's disease
itself is not a fatal disease and many people live into their older years. Mortality of
Parkinson's disease patients is usually related to secondary complications, such as
pneumonia or falling-related injuries.
There are three types of Parkinson's disease and they are grouped by age of
onset:
 Adult-Onset Parkinson's Disease - This is the most common type of

Parkinson's disease. The average age of onset is approximately 60 years
old. The incidence of adult onset PD rises noticeably as people advance
in age into their 70's and 80's.
 Young-Onset Parkinson's Disease - The age of onset is between 21-40
years old. Though the incidence of Young-Onset Parkinson's Disease is
very high in Japan (approximately 40% of cases diagnosed with
Parkinson's disease), it is still relatively uncommon in the U.S., with
estimates ranging from 5-10% of cases diagnosed.
 Juvenile Parkinson's Disease - The age of onset is before the age of 21.
The incidence of Juvenile Parkinson's Disease is very rare.
1.3.1: Symptoms of Parkinson’s disease:
Parkinson’s disease is difficult to diagnose in its early stages. The disease

is diagnosed mostly through symptoms, which may include:
 Tremors (shaking) in the hands, arms, legs, and face.

 Slowness of movement, especially when initiating motion.
 Muscle rigidity.
 Difficulty with walking, balance, and coordination.
 Difficulty in eating and swallowing.

INTRODUCTION
 Digestive problems.
 Speech problems.
 Depression and difficulties with memory and thought processes.
All the types of Parkinsonism occur when nerve cells or neurons, in an area
of the brain known as the substantia nigra in a particular part of the brain (Mid
brain) die or lose the ability to function. These cells normally produce a chemical
called Dopamine, a chemical messenger that helps relay signals to different parts of
the brain. This process is important in producing smooth, coordinated movement
throughout the body. When Dopamine-producing cells (dopaminergic neurons) are
lost, normal movement becomes impossible. In people with late-stage Parkinson's
disease, 80% or more of these important cells are dead or impaired in the substantia
nigra. The cause of this cell death or impairment is not known but significant
findings by research scientists continue to yield fascinating new clues to the disease.
Fig.- 1: Location of substantia nigra in brain and the occurance of parkinson’s

disease.

INTRODUCTION
1.3.2: Treatment:
There is no cure for Parkinson’s disease. Treatments focus on
controlling symptoms and improving quality of life. Drugs, physical therapy,
and surgical interventions can manage Parkinson's disease.
 Medications:- Because Parkinson’s disease symptoms are due to a

deficiency of the brain chemical dopamine, the main drug treatments help
increase dopamine levels in the brain. Levadopa, usually combined with
carbidopa, is the standard drug treatment. For patients who do not respond to
levodopa, dopamine agonists (drugs that mimic the action of dopamine) may
be prescribed. Other types of medication may also be used. Unfortunately,
many of these drugs can cause side effects and lose effectiveness over time.
 Physical Therapy:- Physical therapy is an important part of Parkinson’s

treatment. Rehabilitation can help patients improve their mobility, speech,
and functional abilities.
 Surgery:- In some cases of advanced-stage Parkinson’s disease, surgery

may help to control motor problems. Deep brain stimulation is currently the
preferred surgical method.
The American Academy of Neurology recommends the following therapies

for the initial treatment of Parkinson’s disease:
 Levodopa (L-dopa) :- Levodopa, or L-dopa, has been used for years and is
the gold standard for treating Parkinson's disease. L-dopa increases brain
levels of dopamine. It is probably the most effective drug for controlling
symptoms and is used in nearly all phases of the disease. The standard
preparations (Sinemet, Atamet) combine levodopa with carbidopa, a drug
that slows the breakdown of levodopa. Levodopa is better at improving
motor problems than dopamine agonists but increases the risk of involuntary
movements (dyskinesia). Effectiveness tends to decrease after 4 - 5 years of
usage.

INTRODUCTION
 Selegiline (Eldepryl) and Rasagiline (Azilect):- Selegiline is a monoamine

oxidase B (MAO-B) inhibitor that may have some mild benefit as an initial
therapy. However, unlike levodopa, it does not slow the progression of
Parkinson's disease. Rasagiline (Azilect) is another MAO-B inhibitor used
for treatment of Parkinson’s.
 Dopamine Agonists:- Dopamine agonist drugs mimic dopamine to

stimulate the dopamine system in the brain. These drugs include
pramipexole (Mirapex), ropinirole (Requip), and bromocriptine (Parlodel).
The American Academy of Neurology also finds good evidence for the
dopamine agonist, ropinirole (Requip) and pramipexole (Mirapex), and the
catechol-o-methyl transferase (COMT) inhibitor tolcapone (Tasmar).
Ropinirole (RequipR) is a non-ergoline dopamine D2 receptor agonist (indole

derivative) which has been approved in numerous countries for use in monotherapy
and combination therapy for Parkinson's disease. Although ropinirole is well
tolerated and effective, an extended titration phase and a need for multiple dosages
per day may decrease patient compliance and provide a barrier to optimizing patient
function. Therefore, a simple and rapid titration schedule and a reduction in the
number of daily doses may improve patient compliance and ultimately improve
outcomes.
In an effort to address these needs, an oral osmotic drug delivery of ropinirole

formulation has been developed as a once a day formulation with a simple and faster
dose titration regimen.

Objective
2. OBJECTIVES
The aim of the present work was to design and develop once a daily formulation of
osmotic drug delivery system of ropinirole to improve patient compliance and
thereby therapeutic effectiveness. The specific objective of the work was to:
 Develop once a day dosage form for ropinirole with zero order release rate
kinetics.
 Achieve better patient compliance by reducing the frequency of the dose
administration as compared to conventional therapy.
 Develop cost effective formulation without using sophisticated laser drilling
technology.
 To provide a controlled and extended release of the drug.
 Develop a method suitable for large scale production.

Review Of Literature
3. REVIEW OF LITERATURE
3.1: Review of literature of osmotic drug delivery system:
 Wakode et. al. designed a monolithic osmotically controlled delivery system

of poorly water soluble Nifedipine by direct compression technique. They
investigated the effect of hydrophilic polymers like guar gum and osmogents
like sodium chloride, potassium chloride, spray-dried lactose and fructose.
They compared the in-vitro release data obtained using different types of
coating membranes like controlled porosity membrane, asymmetric
membrane and dense coating membrane with mechanically drilled orifice.
Based on the obtained results they reported that when the concentration of
osmotic agent was increased the solubility of Nifedipine was enhanced and its
release was controlled for 24hr. The drug release profile was found to be
independent of environmental media and agitation rate and was following
zero order kinetics.
 Liu et. al. designed a monolithic osmotic tablet system of poorly water
soluble Nifedipine by direct compression technique and coated with cellulose
acetate. The membrane was drilled on both the side using sharp needles. They
also investigated the effect of variables such as molecular weight and amount
of polyethylene oxide (PEO), amount of osmogent KCl and rice starch. The
optimized formulation was studied for the effect of orifice size and membrane
variables including nature and amount of hydrophobic and hydrophilic
plasticizer (triacetin and polyethylene glycol). They observed that hydrophilic
plasticizer helped to improve the drug release whereas hydrophobic
plasticizer depressed the drug release. The prepared monolithic osmotic tablet
system was found to control the release for 24hr and followed zero order
kinetics.

 Liu et. al. designed a monolithic osmotic tablet system of Atenolol by wet
granulation technique using tartaric acid as solubility promoter, sodium
chloride as osmogent, polyvinyl pyrrolidone as retarding agent, ethyl
cellulose as semipermeable coating membrane and polyethylene glycol 400 as
plasticizer. The prepared monolithic osmotic tablet system was found to
control the release for 24hr and followed zero order kinetics. They also
reported that the approach of solubility enhancement by acid-alkali reaction
between the drug and tartaric acid might be useful for the preparation of
osmotic pump tablet of other poorly water-soluble drugs.
 Pritam et. al. designed a porous osmotic pump drug delivery system for
controlled release of hydrophilic oxybutynin by wet granulation technique
using mannitol as osmogent, PVP K30 as granulating agent, cellulose acetate
as semipermeable and polyethyleneglycol–400 as pore forming/channeling
agent. The prepared porous osmotic pump drug delivery system of
oxybutynin was found to control the release for 20 hr through osmotic
pressure and followed zero order kinetics. They also reported that the drug
release was independent of environmental media and agitation rate.
 Prabhakaran et. al. developed modified push-pull osmotic system for

simultaneous delivery of freely water soluble Theophylline and Salbutamol
by wet granulation technique using double compression method. They also
investigated the effect of variables such as hydroxy propylmethyl cellulose in
upper layer, adhesive agent such as poly ethylene oxide in lower layer,
microcrystalline cellulose, cellulose acetate and polyethyleneglycol–400 as
plasticizer. The modified push-pull osmotic system for simultaneous delivery
was found to control release of both the drugs for an extended period of time
(16 - 20 hrs) through osmotic pressure and was found to be following zero
order kinetics.

 En-xian lu et. al. designed a monolithic osmotic tablet system of water-

insoluble Naproxen by direct compression technique using gum arabic as an
osmotic, suspending, and expanding agent, cellulose acetate as
semipermeable coating membrane and polyethylene glycol 400 as plasticizer
for controlling membrane porosity. The membrane was drilled on both the
side of the tablet using microdrill. The prepared monolithic osmotic tablet
system was found to control the release for 12hr and followed zero order
kinetics.
 Vavia et. al. developed a controlled release monolithic osmotic system of

highly water soluble pseudoephedrine by wet granulation techniques using
sodium bicarbonate as osmogent, lactose as diluent, cellulose acetate as
semipermeable coating membrane, diethyl phthalate, dibutyl phthalate,
dibutyl sebacate and polyethylene glycol 400 as different channeling agents.
The prepared monolithic osmotic tablet system was found to control the
release for 12hr and followed zero order. They also reported that the drug
release was independent of environmental media and agitation rate.
 Gondaliya et. al. formulated and evaluated controlled-porosity osmotic drug

delivery for diltiazem hydrochloride by wet granulation techniques using guar
gum as swellable polymer, sodium chloride as osmogents, as PVP K30 as
granulating agent, cellulose acetate as semipermeable, dibutyl phthalate,
triethyl citrate plasticizers as and glycerin as water insoluble pore-forming
agent. They reported the drug release rate decreased with increasing
concentration of dibutyl phthalate and triethyl citrate, whereas it increased
with increase in the polyethylene glycol 400 concentration. The prepared
bilayered osmotic tablet system was found to control the release for 24 hr and
followed zero order kinetics. They also reported that the drug release was
independent of environmental media and agitation rate.

3.2: DRUG PROFILE:
 Name: Ropinirole Hydrochloride: Ropinirole is a cream-yellowish-white

crystalline powder.
 Brand name: - Requip, ropitor, ropark, ropeway.
 BCS Class: class – I (highly soluble and highly permeable)
 Structural Formula:
 IUPAC NAME: 4-[2-(Dipropylamino) ethyl]-1,3–dihydro–2H-indol–2–one

 Molecular formula: C16H24N2O
 Molecular weight: 296.84 (260.38 as the free base).
 Melting point: 243° to 250°.
 Solubility: It is highly soluble in water (133 g/L).
 Partition Coefficient: Log P (octanol/water):- 2.70.
 Bioavailability: Absolute bioavailability approximately, 50 to 55%. Relative
bioavailability from tablet to an oral solution is 85%.
 Half–life: - 6 hrs.
 Volume of distribution: - 7.5 to 8 L/kg.
 Clearance: - 47 L/h.
 Distribution in blood: - Blood: plasma ratio is 1:1.
 Protein binding: - 10 to 40%.
 Dose: - 3 to 24 mg daily.
Minimum dose: 4 mg/day, Maximum dose: 24mg/day, Taken 1 to 3 hrs
before bed time.

 Estimation: - U.V. Spectrophotometer at 250 nm.
 Mechanism of Action: Ropinirole hydrochloride is a non-ergoline dopamine

agonist with high relative in-vitro specificity and full intrinsic activity at the
D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3
than to D2 or D4 receptor subtypes.
Ropinirole has moderate in-vitro affinity for opioid receptors.
Ropinirole and its metabolites have negligible in-vitro affinity for dopamine
D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and
beta-adrenoreceptors.
 Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination.

 Absorption: T max is 1 to 2 hr. High-fat meal increases T max by 2.5 hrs
and reduces C max by 25%, but does not affect extent of absorption.
Absolute bioavailability is 55%. Steady state is reached within 2 days.
 Distribution: Widely distributed, volume of distribution is 7.5 L/kg.
Up to 40% protein bound.
 Metabolism: Extensively metabolized in liver to inactive metabolite,
CYP1A2 is major enzyme involved in metabolism.
 Elimination: Eliminated in urine (less than 10% as unchanged drug).
Elimination half life is approximately 6 hours. Clearance is 47 L/hr.
 Indication and usage: Treatment of the signs and symptoms of idiopathic

Parkinson disease, treatment of moderate to severe primary Restless Legs
Syndrome (immediate release only).
 Contraindications: Ropinirole hydrochloride tablets are contraindicated for

patients known to have hypersensitivity to the product, pregnancy, nursing
mother, hepatic function, hallucination, cardiovascular disease, major
psychotic disorder.

 Interactions:
 CNS depressants (Ex. alcohol).
 CYP1A2 inducers (Ex. Cigarette smoking, rifampicin).
 CYP1A2 inhibitors (Ex. Ciprofloxacin, erythromycin, fluvoxamine).
 Dopamine antagonists (Ex. Metoclopramide, phenothiazines,

thioxanthenes, butyrophens,).
 Estrogen, Levadopa, Warfarin.
 Adverse reactions: Hypertension, bradycardia, dizziness, migraine, increased

sweating, rash, pharyngitis, xerophthalmia, tooth ache, urinary incontinence,
hematuria, arthritis, back pain, abnormal dreaming etc.

3.3: Hydroxy Propyl Methyl Cellulose (HPMC):
 Nonproprietary Names:
 BP: Hypromellose
 JP: Hydroxypropylmethylcellulose
 EP: Hypromellosum
 USP: Hypromellose
 Synonyms: Benecel MHPC, E464, hydroxypropyl methylcellulose, HPMC,

Methocel, methylcellulose propylene glycol ether, methyl
hydroxypropylcellulose, Metolose, Tylopur.
 Molecular formula: C32H60O19
 Molecular weight: Approx. 10,000 – 15, 00,000
 Chemical Name: Cellulose hydroxypropyl methyl ether.
 Description: HPMC is an odorless and tasteless, white or creamywhite

fibrous or granular powder.

 Typical Properties:
 Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous solution.
 Bulk Density: 0.341 g/cm3
 Tapped Density: 0.557 g/cm3
 Melting point: browns at 190–200ºC, chars at 225-230oC.
 Glass transition temperature: 170–180ºC.
 Solubility: soluble in cold water, forming a viscous colloidal solution;

practically insoluble in chloroform, ethanol (95%), and ether, but soluble in
mixtures of ethanol and dichloromethane, mixtures of methanol and
dichloromethane, and mixtures of water and alcohol. Certain grades of
hypromellose are soluble in aqueous acetone solutions, mixtures of
dichloromethane and propan-2-ol, and other organic solvents.
 Applications: Suspending and/or thickening agent, extended-release agent,

sustained-release agent, controlled-release agent, film forming agent, tablet
binder.
 Stability & storage conditions: HPMC powder is a stable material, although

it is hygroscopic after drying. Hypromellose powder should be stored in well-
closed container, in a cool, dry place.
 Incompatibilities: HPMC is incompatible with some oxidizing agents. Since

it is non-ionic, hypromellose will not complex with metallic salts or ionic
organics to form insoluble precipitates.

3.4: Cellulose, Microcrystalline:
 BP: Microcrystalline Cellulose,
 JP: Microcrystalline Cellulose
 EP: Cellulose, Microcrystalline
 USP-NF: Microcrystalline Cellulose
 Synonyms: Avicel PH, Cellets, Celex, cellulose gel, hellulosum

microcristallinum; Celphere; Ceolus KG, crystalline cellulose, E460,
Emcocel, Ethispheres, Fibrocel, MCC Sanaq, Pharmacel, Tabulose, Vivapur.
 Molecular Formula: (C6 H10 O5)n where n = 220.

 Molecular Weight: 36 000
 Chemical Name :Cellulose
 Description: Microcrystalline cellulose is purified, partially depolymerized

cellulose that occurs as a white, odorless, tasteless, crystalline powder
composed of porous particles. It is commercially available in different particle
sizes and moisture grades that have different properties and applications.

 Acidity/alkalinity: pH =5–7.5 for a 1.2% w/v aqueous dispersion.
 Bulk Density: 0.337 g/cm3.
 Tapped Density: 0.478 g/cm3.
 Melting point: chars at 260–270ºC.
 Solubility: Slightly soluble in 5% w/v sodium hydroxide solution; practically

insoluble in water, dilute acids, & most organic solvents.
 Applications: Microcrystalline cellulose is widely used in pharmaceuticals,

primarily as a binder/diluent in oral tablet and capsule formulations where it is
used in both wet-granulation and direct-compression processes. It is also used
as a lubricant and disintegrant properties that make it useful in tableting.
Microcrystalline cellulose is also used in cosmetics and food products.
 Stability and Storage Conditions: Microcrystalline cellulose is a stable

though hygroscopic material. The bulk material should be stored in a well-
closed container in a cool, dry place.
 Incompatibilities: Microcrystalline cellulose is incompatible with strong

oxidizing agents.

3.5: Sodium chloride
 BP: Sodium chloride
 JP: Sodium chloride
 EP: Natrii chloridum
 USP: Sodium chloride
 Synonyms: Alberger, chlorure de sodium, common salt, hopper salt, natural

halite, rock salt, saline, salt, sea salt, table salt.
 Chemical Name: Sodium chloride.

 Molecular Formula: Nacl.
 Molecular Weight: 58.4
 Structural Formula: Nacl
 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 0ºC, salt may crystallize as a dihydrate.
 Acidity/alkalinity: pH = 6.7–7.3 (saturated aqueous solution)
 Melting point: 804ºC
 Solubility: Slightly soluble in ethanol, 1 in 250 Ethanol (95%), 1 in 10

Glycerin, 1 in 2.8, 1 in 2.6 at 100ºC Water.

 Applications: Sodium chloride is widely used in a variety of parenteral and

non-parenteral pharmaceutical formulations, where the primary use is to
produce isotonic solutions. Sodium chloride has been used as a lubricant and
diluent in capsules and direct-compression tablet formulations.
Sodium chloride has also been used as a channelling agent and as an
osmotic agent in the cores of controlled-release tablets. It has been used as a
porosity modifier in tablet coatings, and to control drug release from
microcapsules.
 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-closed
container, in a cool, dry place.
 Incompatibilities: Aqueous sodium chloride solutions are corrosive to iron.

They also react to form precipitates with silver, lead, and mercury salts.
Strong oxidizing agents liberate chlorine from acidified solutions of sodium
chloride. The solubility of the antimicrobial preservative methylparaben is
decreased in aqueous sodium chloride solutions and the viscosity of carbomer
gels and solutions of hydroxyethyl cellulose or hydroxypropylcellulose is
reduced by the addition of sodium chloride.

3.6: Potassium Chloride:
 BP: Potassium chloride
 JP: Potassium chloride
 EP: Kalii chloridum
 USP: Potassium chloride
 Synonyms: Chloride of potash, chloropotassuril, dipotassium dichloride,

E508, potassium monochloride.
 Chemical Name: Potassium chloride

 Molecular Formula: KCl
 Structural Formula: KCl
 Description: Potassium chloride occurs as odorless, colorless crystals or a

white crystalline powder, with an unpleasant, saline taste. The crystal lattice is
a face-centered cubic structure.
 Acidity/alkalinity: pH ≈ 7 for a saturated aqueous solution at 15ºC.
 Bulk Density: 1.17 g/cm3, for a saturated aqueous solution at 15ºC.
 Tapped Density: 1.99 g/cm3, for a saturated aqueous solution at 15ºC.
 Solubility: Acetone Practically insoluble, Ethanol (95%) 1 in 250, Ether

Practically insoluble, Glycerin 1 in 14, Water 1 in 2,1 in 1.8 at 100ºC.
 Applications: Potassium chloride is widely used in a variety of parenteral,

ophthalmic preparations and non-parenteral pharmaceutical formulations.

Potassium chloride is also used therapeutically in the treatment of

hypokalemia.
Many solid-dosage forms of potassium chloride exist including: tablets
prepared by direct compression and granulation, effervescent tablets, coated,
sustained-release tablets, sustained-release wax matrix tablets, microcapsules
pellets, as an osmotic agent in the cores of controlled-release tablets and
osmotic pump formulations. Potassium chloride is also used widely in the
food industry as a dietary supplement, pH control agent, stabilizer, thickener,
and gelling agent. It can also be used in infant formulations.
 Stability and Storage Conditions: Potassium chloride tablets become

increasingly hard on storage at low humidities. However, tablets stored at
76% relative humidity showed no increase or only a slight increase in
hardness. The addition of lubricants, such as 2% w/w magnesium stearate,
reduces tablet hardness and hardness on aging. Aqueous potassium chloride
solutions may be sterilized by autoclaving or by filtration. Potassium chloride
is stable and should be stored in a well closed container in a cool, dry place.
 Incompatibilities: Potassium chloride reacts violently with bromine tri-

fluoride and with a mixture of sulfuric acid and potassium permanganate. The
presence of hydrochloric acid, sodium chloride, and magnesium chloride
decreases the solubility of potassium chloride in water. Aqueous solutions of
potassium chloride form precipitates with lead and silver salts. Intravenous
aqueous potassium chloride solutions are incompatible with protein
hydrolysate.

3.7: Dextrose:
 BP: Glucose monohydrates
 JP: Glucose
 EP: Glucosum monohydricum
 USP: Dextrose
 Synonyms: anhydrous dextrose, anhydrous D-(+)-glucopyranose, anhydrous

glucose, dextrosum anhydricum.
 Molecular Formula: C6 H12 O6

 Chemical Name: D-(+)-Glucose anhydrous.
 Description: Dextrose occurs as white, odorless, crystalline powder with a

sweet taste.
 Acidity/alkalinity: pH = 3.5–5.5 (20% w/v aqueous solution)
 Bulk Density: 1.1–1.2 g/cm3
 Tapped Density: 1.3–1.4 g/cm3

 Solubility: Ethanol (95%), Ether Sparingly soluble, Methanol 1 in 120, Water

1 in 1.1 at 25ºC, 1 in 0.8 at 30ºC, 1 in 0.41 at 50ºC, 1 in 0.28 at 70ºC,1 in 0.18
at 90ºC.
 Applications: Dextrose is widely used in solutions to adjust tonicity and as a

sweetening agent. Dextrose is also used as a wet granulation diluent and
binder, and as a direct-compression tablet diluent and binder, primarily in
chewable tablets, as an osmotic agent in the cores of controlled-release
tablets and osmotic pump formulations. The mildly reducing properties of
dextrose may be used when tableting to improve the stability of active
materials that are sensitive to oxidation. Dextrose is also used therapeutically
and is the preferred source of carbohydrate in parenteral nutrition regimens.
 Stability and Storage Conditions: Dextrose has good stability under dry
storage conditions. Aqueous solutions may be sterilized by autoclaving.
However, excessive heating can cause a reduction in pH and caramelization
of solutions. The bulk material should be stored in a well-closed container in
a cool, dry place.
 Incompatibilities: Dextrose solutions are incompatible with a number of

drugs such as cyanocobalamin, kanamycin sulfate, novobiocin sodium, and
warfarin sodium. Erythromycin gluceptate is unstable in dextrose solutions at
a pH less than 5.05. Decomposition of B-complex vitamins may occur if they
are warmed with dextrose. In the aldehyde form, dextrose can react with
amines, amides, amino acids, peptides, and proteins. Brown coloration and
decomposition occur with strong alkalies.

3.8: Magnesium Stearate:
 BP: Magnesium stearate
 JP: Magnesium stearate
 EP: Magnesii stearas
 USPNF: Magnesium stearate
 Synonyms: Magnesium octadecanoate, octadecanoic acid, magnesium salt,

stearic acid, magnesium salt.
 Chemical Name: Octadecanoic acid magnesium salt.

 Molecular Formula: C36H70 MgO4
 Structural Formula: [CH3(CH2)16COO]2Mg
 Melting range: 117–150ºC (commercial samples), 126–130ºC (high
purity magnesium stearate).
 Solubility: practically insoluble in ethanol, ethanol (95%), ether and water;

slightly soluble in warm benzene and warm ethanol (95%).
 Description: Magnesium stearate is a very fine, light white, precipitated or

milled, impalpable powder of low bulk density, having a faint odour of stearic
acid and a characteristic taste. The powder is greasy to the touch and readily
adheres to the skin.

 Applications: Magnesium stearate is widely used in cosmetics, foods, and

pharmaceutical formulations. It is primarily used as a lubricant in capsule and
tablet manufacture at concentrations between 0.25% and 5.0% w/w. It is also
used in barrier creams.
 Stability and Storage Conditions: Magnesium stearate is stable and should

be stored in a well closed container in a cool, dry place.
 Incompatibilities: Incompatible with strong acids, alkalies, and iron salts.

Avoid mixing with strong oxidizing materials. Magnesium stearate cannot be
used in products containing aspirin, some vitamins, and most alkaloidal salts.

3.9: Poly vinyl pyrrolidone:

 BP: Povidone
 JP: Povidone
 EP: Povidonum
 USP: Povidone
 Synonyms: E1201; Kollidon, Plasdone, poly[1-(2-oxo

1pyrrolidinyl)ethylene], polyvidone poly vinyl pyrrolidone, PVP; 1-vinyl-2-
pyrrolidinone polymer.
 Molecular Formula: (C6 H9 NO)n

 Molecular Weight: 2500-3,00,0000
 Chemical Name: 1-Ethenyl-2-pyrrolidinone homopolymer
 Description: Povidone occurs as a fine, white to creamy-white coloured,

odorless or almost odorless, hygroscopic powder. Povidone with K-values
equal to or lower than 30 are manufactured by spray-drying and occur as
spheres. Povidone K-90 and higher K-value Povidone are manufactured by
drum drying and occur as plates.

 Acidity/alkalinity: pH = 3.0–7.0 (5% w/v aqueous solution).

 Bulk Density: 0.29–0.39 g/cm3
 Tapped Density: 0.39–0.54 g/cm3
 Melting point: softens at 150ºC.
 Solubility: Freely soluble in acids, chloroform, ethanol (95%), ketones,

methanol, and water; practically insoluble in ether, hydrocarbons, and mineral
oil. In water, the concentration of a solution is limited only by the viscosity of
the resulting solution, which is a function of the K-value.
 Applications: Although povidone is used in a variety of pharmaceutical

formulations, it is primarily used in solid-dosage forms. In tableting, povidone
solutions are used as binders in wet granulation processes. Povidone is also
added to powder blends in the dry form and granulated in situ by the addition
of water, alcohol, or hydro-alcoholic solutions. Povidone is used as a
solubilizer in oral and parenteral formulations and has been shown to enhance
dissolution of poorly soluble drugs from solid-dosage forms. Povidone
solutions may also be used as coating agents. Povidone is additionally used as
a suspending, stabilizing, or viscosity-increasing agent in a number of topical
and oral suspensions and solutions. The solubility of a number of poorly
soluble active drugs may be increased by mixing with povidone. Special
grades of pyrogen-free povidone are available and have been used in
parenteral formulations.
 Stability and Storage Conditions: Povidone darkens to some extent on

heating at 150ºC, with a reduction in aqueous solubility. It is stable to a short
cycle of heat exposure around 110–130ºC, steam sterilization of an aqueous
solution does not alter its properties. Aqueous solutions are susceptible to
mold growth and consequently require the addition of suitable preservatives.
Povidone may be stored under ordinary conditions without undergoing
decomposition or degradation. However, since the powder is hygroscopic, it
should be stored in an airtight container in a cool, dry place.

 Incompatibilities: Povidone is compatible in solution with a wide range of

inorganic salts, natural and synthetic resins, and other chemicals. It forms
molecular adducts in solution with sulfathiazole, sodium salicylate, salicylic
acid, Phenobarbital, tannin, and other compounds. The efficacy of some
preservatives, e.g. thimerosal, may be adversely affected by the formation of
complexes with povidone.

3.10: Cellulose Acetate:
 BP: Cellulose acetate
 EP: Cellulosi acetas
 USPNF: Cellulose acetate
 Synonyms: Acetyl cellulose, cellulose diacetate, cellulose triacetate.

 Molecular Formula: [C5 H9 O3R2]n
 Molecular Weight: 30000 – 40000.
 Chemical Name: Cellulose acetate, Cellulose diacetate, Cellulose triacetate.
 Description: Cellulose acetate occurs as a white to off-white powder, free

flowing pellets, or flakes. It is tasteless and odorless, or may have a slight
odour of acetic acid.

 Bulk Density: 0.3 g/cm3 for powders.
 Tapped Density: 0.4 g/cm3 for powders.
 Melting point: melting range 230–300ºC.
 Solubility: The solubility of cellulose acetate is greatly influenced by the

level of acetyl groups present. In general, cellulose acetates are soluble in
acetone–water blends of varying ratios, dichloromethane–ethanol blends,
dimethyl formamide, and dioxane. The cellulose acetates of higher acetyl
level are generally more limited in solvent choice than are the lower-acetyl
materials.
 Applications: Cellulose acetate is widely used in pharmaceutical

formulations both in sustained-release applications and for taste masking.
Cellulose acetate is used as a semipermeable 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 offer sustained release without the necessity of drilling a hole
in the coating as is typical with osmotic pump systems. Cellulose acetate has
also been used to form drug-loaded microparticles with controlled-release
characteristics. Cellulose acetate films are used in transdermal drug delivery
systems and also as film coatings on tablets or granules for taste masking.
Extended-release tablets can also be formulated with cellulose acetate as a
directly compressible matrix former. The release profile can be modified by
changing the ratio of active to cellulose acetate and by incorporation of
plasticizer, but was shown to be insensitive to cellulose acetate molecular
weight and particle size distribution. Therapeutically, cellulose acetate has
been used to treat cerebral aneurysms, and also for spinal perimedullary
arteriovenous fistulas.

 Stability and Storage Conditions: Cellulose acetate is stable if stored in a

well-closed container in a cool, dry place. Cellulose acetate hydrolyzes
slowly under prolonged adverse conditions such as high temperature and
humidity, with a resultant increase in free acid content and odour of acetic
acid.
 Incompatibilities: Cellulose acetate is incompatible with strongly acidic or

alkaline substances. Cellulose acetate is compatible with the following
plasticizers: diethyl phthalate, triacetin, and triethyl citrate.

3.11: Polyethylene Glycol:
 BP: Macrogols
 JP: Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000,
Macrogol 20000.
 EP: Macrogola
 USPNF: Polyethylene glycol.
 Synonyms: Carbowax, Carbowax Sentry, Lipoxol, Lutrol E, PEG, Pluriol E,

polyoxyethylene glycol.
 Molecular Formula: HOCH2(CH2OCH2)mCH2OH

Where, m represents the average number of oxyethylene
groups.
Alternatively, the general formula H (OCH2CH2)n OH may be used to
represent polyethylene glycol.
Where, n is a number m in the previous formula + 1.
 Molecular Weight: 380 - 420.

 Chemical Name: a-Hydro-o-hydroxypoly (oxy-1, 2-ethanediyl)

 Description: The USPNF 23 describes polyethylene glycol as being an

addition polymer of ethylene oxide and water. Poly ethylene glycol grades
200–600 are liquids, grades 1000 and above are solids at ambient
temperatures. Liquid grades (PEG 200–600) occur as clear, colorless or
slightly yellow-colored, viscous liquids. They have a slight but characteristic
odour and a bitter, slightly burning taste. PEG 600 can occur as a solid at
ambient temperatures. Solid grades (PEG>1000) are white or off-white in
colour, and range in consistency from pastes to waxy flakes. They have a
faint, sweet odour. Grades of PEG 6000 and above are available as free-
flowing milled powders.
 Acidity/alkalinity: pH = 4.0–7.0
 Density: 1.11–1.14 g/cm3 at 25ºC for liquid PEG.
 Melting point: 37-63ºC.
 Solubility: All grades of polyethylene glycol are soluble in water and

miscible in all proportions with other polyethylene glycols (after melting, if
necessary). Aqueous solutions of higher-molecular-weight grades may form
gels. Liquid polyethylene glycols are soluble in acetone, alcohols, benzene,
glycerine, and glycols. Solid polyethylene glycols are soluble in acetone,
dichloromethane, ethanol (95%), and methanol, they are slightly soluble in
aliphatic hydrocarbons and ether, but insoluble in fats, fixed oils, and mineral
oil.
 Applications: Polyethylene glycols (PEGs) are widely used in a variety of

pharmaceutical formulations including parenteral, topical, ophthalmic, oral,
and rectal preparations. It has been used experimentally in biodegradable
polymeric matrices used in controlled-release systems. Polyethylene glycols
are stable, hydrophilic substances that are essentially non-irritant to the skin.
They do not readily penetrate the skin, although the polyethylene glycols are
water-soluble and are easily removed from the skin by washing, making them
useful as ointment bases. Solid grades are generally employed in topical

ointments, with the consistency of the base being adjusted by the addition of
liquid grades of polyethylene glycol. Aqueous polyethylene glycol solutions
can be used either as suspending agents or to adjust the viscosity and
consistency of other suspending vehicles. When used in conjunction with
other emulsifiers, polyethylene glycols can act as emulsion stabilizers. Liquid
polyethylene glycols are used as water-miscible solvents for the contents of
soft gelatin capsules. Polyethylene glycols can also be used to enhance the
aqueous solubility or dissolution characteristics of poorly soluble compounds
by making solid dispersions with an appropriate polyethylene glycol. Animal
studies have also been performed using polyethylene glycols as solvents for
steroids in osmotic pumps. In film coatings, solid grades of polyethylene
glycol can be used alone for the film-coating of tablets or can be useful as
hydrophilic polishing materials. Solid grades are also widely used as
plasticizers in conjunction with film-forming polymers. The presence of
polyethylene glycols in film coats, especially of liquid grades, tends to
increase their water permeability and may reduce protection against low pH in
enteric-coating films. Polyethylene glycols are useful as plasticizers in
microencapsulated products to avoid rupture of the coating film when the
microcapsules are compressed into tablets.
 Stability and Storage Conditions: Polyethylene glycols are chemically

stable in air and in solution, although grades with a molecular weight less than
2000 are hygroscopic. Polyethylene glycols do not support microbial growth,
and they do not become rancid. Polyethylene glycols and aqueous
polyethylene glycol solutions can be sterilized by autoclaving, filtration, or
gamma-irradiation. Sterilization of solid grades by dry heat at 150ºC for 1
hour may induce oxidation, darkening, and the formation of acidic
degradation products. Ideally, sterilization should be carried out in an inert
atmosphere. Oxidation of polyethylene glycols may also be inhibited by the
inclusion of a suitable antioxidant. If heated tanks are used to maintain
normally solid polyethylene glycols in a molten state, care must be taken to
avoid contamination with iron, which can lead to discoloration. The
temperature must be kept to the minimum necessary to ensure fluidity;

oxidation may occur if polyethylene glycols are exposed for long periods to
temperatures exceeding 50ºC. However, storage under nitrogen reduces the
possibility of oxidation. Polyethylene glycols should be stored in well-closed
containers in a cool, dry place. Stainless steel, aluminum, glass, or lined steel
containers are preferred for the storage of liquid grades.
 Incompatibilities: However, all grades can exhibit some oxidizing activity

owing to the presence of peroxide impurities and secondary products formed
by autoxidation. Liquid and solid polyethylene glycol grades may be
incompatible with some colouring agents. The antibacterial activity of certain
antibiotics is reduced in polyethylene glycol bases, particularly that of
penicillin and bacitracin. The preservative efficacy of the parabens may also
be impaired owing to binding with polyethylene glycols. Physical effects
caused by polyethylene glycol bases include softening and liquefaction in
mixtures with phenol, tannic acid, and salicylic acid.

Methodology
4. METHODOLOGY
Table 5: List of materials used for the study:
Material Grade Manufacturer
Ropinirole I.P. Dr.Reddy’s generics
research and
development, Hyderabad.
HPMC K4M I.P. Colorcon PVT. LTD.
Verna Goa.
HPMC K 100 M I.P. Colorcon PVT. LTD.
Verna Goa.
Micro crystalline I.P. s.d.fine- Chem limited,
cellulose(MCC) Mumbai.
Sodium chloride I.P. s.d.fine- Chem limited,
(NaCl) Mumbai.
Magnesium Sterate I.P. s.d.fine- Chem limited,
Mumbai.
Polyvinylpyrrolidone I.P. Sunrise remedies PVT.
(PVP K30) LTD. Ahmedabad.
Cellulose Acetate U.S.P. Sigma Aldrich chemicals,
U.S.A.

Methodology
Table 6: List of instruments:
Instruments Manufacturer
Weighing Balance Dhona instrument Pvt. Ltd. Kolkata.
Weighing Balance Shimadzu BL-220H, Shimadzu

Corporation, Japan.
Rotary Tablet Press Rimek RSB-4 Minipress, Karnavati
Engineering Ltd, Ahmedabad, India.
Coating pan Rimek Kalweka, Karnavati Engineering
Ltd, Ahmedabad, India.
Digital pH meter – 707 Digisun Electronics, Hyderabad.
UV-Visible Spectrophotometer Shimadzu UV-1700 PC, Shimadzu

Corporation, Japan.
FTIR Spectrometer Jasco 460 Plus, Japan.
USP XXIII Dissolution Tester TDT – 08L, Electrolab, India.
Bulk Density Apparatus Campbell Electronics, India.
Friabilator Electrolab EF-2, India.
Tablet Hardness Tester (Monsanto type)
Humidity chamber Thermolab scientific instrument, Pvt.

Limited.

Methodology
4.1: Scanning of Ropinirole in different solvent system:

The solution containing 10µg/ml of Ropinirole was prepared in different
solvent (0.1 N HCl, Distilled water, Phosphate buffer pH6.8, Phosphate buffer
pH7.4) and scanned over the wavelength range of 200-400 nm using double beam
UV spectrophotometer.
4.2: Calibration curve of Ropinirole in different solvent system:

An accurately weighed quantity (100mg) of Ropinirole was transferred in 100
ml volumetric flask and dissolved in distilled water and made up to 100 ml to
produce a primary stock solution of concentration 1mg/ml. From this, 1ml was
withdrawn and diluted to 50ml to get a concentration of 20µg/ml. It was further
diluted to get concentration in the range of 2-10µg/ml. The absorbance of the
solution was recorded at 249.5nm using double beam U.V. spectrophotometer
against water as a blank. The plots of absorbance versus concentration were plotted.
Similarly, calibration curve was also constructed in 0.1 N HCl, pH6.8 phosphate
buffer, pH7.4 phosphate buffer.
4.3: Drug-Excipient interaction study:
Infrared spectroscopy and differential scanning calorimetry are useful analytical

technique utilized to check the chemical interaction between the drug & other
excipients used in the formulation.
4.3.1: Fourier Transform Infra Red (FTIR) spectroscopy:
Infrared spectroscopy is a useful analytical technique utilized to check the

chemical interaction between the drug & other excipients used in the formulation.
First an accurately weighed quantity of drug and other excipients were properly
mixed. One milligram of the sample was taken and mixed with 10 mg of dry
powdered potassium bromide. The powdered mixture was taken in a diffuse
reflectance sampler & the spectrum was recorded by scanning in the wavelength
region of 4000-400 cm-1 in an FTIR spectrophotometer (Jasco 460 Plus, Japan). The
IR spectrum of the drug was compared with that of the physical mixture to check for
any possible drug-excipients interaction.
Methodology
4.3.2: Differential scanning calorimetry:
Differential scanning calorimetry is a useful analytical technique utilized to

check the chemical interaction between the drug & other excipients used in the
formulation. Mettler-toledo instrument was used.
In differential scanning calorimetry (DSC), sample and reference materials

were placed in separate pans and the temperature of each pan was increased or
decreased at a predetermined rate. When the sample reached its melting point, it
remained at this temperature until all the material has passed in to the liquid state,
because of the endothermic process of melting. A temperature difference therefore
exists between sample and reference, indium, as the temperature of the two materials
was raised gradually. A second temperature circuit was used in DSC to provide a
heat input to overcome this temperature difference.
The difference is heat input the sample and the reference per unit time is fed to
a recorder and plotted as dH/dt versus the average temperature to which the sample
and reference are being raised.
4.4: Dose calculation for controlled release osmotic tablets of Ropinirole:
 Practical dose calculation of ropinirole.

 Theoretical drug release calculation of ropinirole.
4.4.1: Practical dose calculation of ropinirole:
The practical dose of Ropinirole for once a daily controlled release

formulation was calculated total dose by the following equation using
pharmacokinetic data.
Total dose of drug: DT = DL + DM.......... (1)

Where,
DL= Loading dose.
DM = Maintenance dose.

Methodology
4.4.2: Theoretical drug release calculation of Ropinirole:
The theoretical dose calculation of Ropinirole for once a daily controlled

release formulation was calculated total dose by the following equation using
pharmacokinetic data.
Total dose of drug: DT = DL + DM........... (2)
Where,
DL = Loading dose.
DM = Maintenance dose.
4.5: Formulation of controlled release osmotic tablets:
 Formulation of Core tablet

 Coating of the core tablet
The core tablets were prepared by two methods, direct compression method and wet
granulation method.
4.5.1: Preparation of core tablet by direct compression:
In the initial trials (F1 – F2), the tablets were prepared by direct compression
method using varying concentration of polymer and osmoagent.
Drug (Ropinirole) and other excipients like swellable polymer, binder,

osmoagent and lubricant were weighed accurately and passed through the sieve
no. # 20. The ingredients were properly mixed in mortar and compressed into
tablets using 8.5 mm concave punch in Rimek RSB -4 Minipress. The average
weight of the tablets was kept at 250 mg.

Methodology
Table 7: Composition of formulation F1 – F3:
Ingredients F1 F2 F3
(mg)
Ropinirole 3 3 3
HPMC K 100 60 - 68
HPMC K4M - 85 -
MCC 170 150 170
Nacl 15 10 7
Mg.Sterate 2 2 2
4.5.2: Preparation of core tablet by wet granulation method:
Formulation F4 and F5 were prepared by wet granulation method using

alcoholic solution of PVP K30 as granulating agents.
Drug (Ropinirole) and other excipients like swellable polymer, binder,

different osmogent, and lubricant were weighed accurately and properly mixed
in mortar. Alcoholic solution PVP K30 was incorporated to the blend and
granulating for 15 minutes. The wet mass was passed through sieve no. # 20 &
dried at room temperature initially and then in hot air oven at 60ºC for 10
minutes. The blend was compressed into tablets of 250 mg using 8.5 mm
concave punch in Rimek RSB -4 Minipress.
Formulation F6 and F7 were prepared using7% w/w of potassium chloride

and dextrose respectively, to study the effect of various osmogents on the
release. These tablets were also prepared by wet granulation method as
specified earlier.

Methodology
Table 8: Composition of formulation F-4 to F-7:
Ingredients F-4 F-5 F-6 F-7

(mg)
Ropinirole 3 3 3 3
HPMC K4M 100 75 75 75
MCC 88 113 113 113
Nacl 7 7 - -
KCl - - 7 -
Dextrose - - - 7
Mg.Sterate 2 2 2 2
PVP K 30 50 50 50 50
4.5.3: Coating of tablet:
The core tablets were coated in a conventional coating pan by spraying the
solution. The coating process parameters were optimized with respect to coating pan
speed, distance of spray gun from centre of coating pan, coating pan temperature,
nozzle pressure and coating solution spraying rate. The parameters used for coating
purpose are mentioned below:
 Coating pan speed:- 15 rpm

 Distance of spray gun from centre of coating pan:- 18cm
 Coating pan temperature:- 40-450C.
 Spray gun:- type 64M (Pilot scale)
 Nozzle pressure:- 30 lb/inch2 or 3Kg/cm2
 Spray rate:- 3ml/minute
 Controlled porosity coating:- The coating solution was prepared by

completely dissolving 2gm of cellulose acetate (39.8 % acetyl content) in 100
ml acetone, to which 0.4 gm of PEG-400 was added as pore forming agent.
The coating solution was spread on the tablets (F4 – F5) in the coating pan

Methodology
with intermittent drying. The coating solution was sprayed to get a weight
gain 5% of the total tablet weight.
 Dense coating:- Tablets of formulation F5 was coated with 2% cellulose
acetate (39.8 % acetyl content) completely dissolved in acetone without any
poreforming agents. The coating solution was spreyed onto the tablets with
intermittent drying. The tablets were to get 5% wet gain of the total tablet
weight. The coating solution was sprayed to get a weight gain 5% of the total
tablet weight.
 Mechanical drilling:- Formulation F5 to which dense coating was applied,

was mechanically drilled using 26-guage needle having 0.2 mm diameter to
get an orifice which would facilitate the drug release.
4.6: Evaluation of controlled release osmotic tablets:

 Precompression parameters.
 Post compression parameters.
4.6.1: Precompression parameters:

The granules were evaluated for bulk density, tapped density, Carr’s index,
Hausner’s ratio & angle of repose.
a) Bulk density:
The powder sample under test was screened through sieve # 18 & the
sample equivalent to 10g was accurately weighed, filled in a 50 ml graduated
cylinder, the powder was levelled & the unsettled volume (V0) was noted. The
bulk density was calculated in g/cm3 by the formula,
Bulk density (ρb) = M / V0.......... (3)
Where,
M = Mass of powder taken.
V0= Apparent unstirred volume.

Methodology
b) Tapped density:
The powder sample under test was screened through sieve # 18 & the
weight of sample equivalent to 10g was filled in 50 ml graduated cylinder.
The mechanical tapping of the cylinder was carried out using tapped density
tester at a constant rate for 100 times. Volume was considered as tapped
volume (Vf). The tapped density was calculated in g/cm3 by the formula,
Tapped density (ρt) = M / Vf .......... (4)
Where,
M = Weight of sample powder taken.
Vf = Tapped volume.
c) Percentage compressibility or Carr’s index:
Based on the bulk density & tapped density, the percentage

compressibility of the granules was computed using the Carr’s compressibility
index by the formula,
Carr’s index = Tapped density – Bulk density × 100………. (5)

Tapped density
Table 9: Carr’s index as an indication of powder flow:
Carr’s Index (%) Flow
5-10 Excellent
12-16 Good
18-21 Fair to passable*
23-35 Poor*
33-38 Very poor
>40 Extremely poor
*May be improved by glidant, e.g. 0.2% Aerosil

Methodology
d) Hausner’s ratio:
Hausner’s ratio was calculated using the formula,
Hausner’s ratio = tapped density/bulk density.......... (6)
Table 10: Values of Hausner’s ratio:
Values (%) Comments
Less than 1.25 Good flow
Greater than 1.5 Poor flow
Between 1.25-1.5 Addition of glidant normally

improves the flow
e) Angle of repose:
Angle of repose of the granules was determined by the height cone

method. A funnel was fixed to a desired height & granules were filled in it.
They were allowed to flow down on a graph paper fixed on a horizontal
surface & angle of repose was calculated using the formula,
tan θ = h/r............... (7)
Where,
h = Height of the pile respectively,
r = Radius ( area of pile).
Table 11: Angle of repose as an indication of powder flow properties:
Angle of repose (degrees) Type of flow
< 20 Excellent
20-30 Good
30-34 Passable*
> 40 Very poor
*May be improved by glidant, e.g. 0.2% Aerosil

Methodology
f) Co-efficient of friction:
Based on the angle of repose, the co-efficient of friction was calculated

using the formula
µ = tan θ.......... (8)
4.6.2: Post compression parameters:

The tablets were evaluated for thickness, hardness, friability, weight
variation test, drug content, in- vitro dissolution study.
All the prepared controlled release osmotic tablets were evaluated for the
following parameters.
a) Hardness:
The tablet hardness is defined as the force required for breaking a tablet
in a diametric compression test. To perform this test, a tablet is placed
between two anvils, force is applied to the anvils & the crushing strength that
just causes the tablet to break is recorded. The hardness was measured using
Monsanto hardness tester. It is expressed in Kg/cm2.
b) Friability:
The friability of the tablets was determined using Roche friabilator. It
is expressed in percentage (%). Approximately 6 g (W0) of tablets were
subjected to 100 free falls of 6 inches in a rotating drum & were then
reweighed (W). The friability, f, is given by:
f = 100 × (1 – W/W0).......... (9)
This test is performed to measure the mechanical strength of the tablet.

It helps know whether a tablet could withstand the stress during packing and
transportation.

Methodology
c) Weight variation test:
Twenty tablets were weighed individually, average weight was

calculated & individual tablet weights were compared to the average weight.
The tablets meet the USP test if no more than 2 tablets are outside the
percentage limit & if no tablet differs by more than two times the percentage
limit.
Table 12: Weight variation tolerances for uncoated tablets:
Average weight of tablets (mg) Maximum percentage difference

allowed
130 or less 10
130-324 7.5
More than 324 5
4.7: Drug content:
Ten tablets were weighed and average weight was calculated. All tablets were
crushed in mortar. The powder equivalent to 250 mg was accurately weighed,
dissolved in dissolution media & the volume was made up to 250 ml with respective
dissolution media. The solution was then filtered and the absorbance was recorded at
249.5nm using double beam UV spectrophotometer against dissolution media as a
blank. The amount of drug present in one tablet was calculated.

Methodology
4.9: Effect of dissolution media and rpm on In-Vitro release of the drug:
The release of Ropinirole from osmotic tablets was determined using USP type II
dissolution apparatus (paddle type). The dissolution test was performed by using 250 ml of
dissolution media (0.1N HCl/ water/ phosphate buffer pH6.8 / phosphate buffer pH7.4 ) at
37oC ± 0.5oC and at different rpm (50, 75, 100). Sample of 5 ml was withdrawn from the
dissolution basket after every 1hour and equal volume of fresh dissolution medium was
added to maintain the volume constant. The absorbance of the solution was recorded at
249.5nm using Shimadzu UV-1700 double beam UV spectrophotometer (Shimadzu,
Japan) against respective dissolution media as a blank. A plot of percentage cumulative
drug release calculated from the obtained absorbance values versus time was plotted.
4.9: Dissolution data treatment using different kinetic models:
To analyze the in-vitro release data, various kinetic models were used to
describe the release kinetics. The drug release profile obtained in dissolution test
was plotted in different models.
4.9.1: Zero order rate kinetics describes the system where the drug release rate
is independent of concentration and plotted as amount of drug release versus
time.
C=K0t.......... (10)
Where,
K0 is the zero order rate constant, Expressed in units of
concentration/ time.
t is the time in hours.
4.9.2: First order rate kinetics describes the release from system where release
rate is concentration dependent and shows the log cumulative percentage of drug
remaining in insoluble matrix as a time dependent process. (log% drug remained
v/s time in hr)
log C = log C0 - kt/2.303..........(11)
Where,
Methodology
C0 is the initial drug concentration.

C is the drug concentration at time t.
K is the first order rate constant reflecting the design variables of the
system.
t is the time in hours.
4.9.3: Higuchi square root kinetics describes the release of drug from insoluble
matrix as a square root of time dependent process based on Fickian diffusion
equation. (%cumulative release v/s square root of time).
Q=Kt½.......... (12)
Where,
Q is the percentage of drug release at time t.
K is Higuchi release rate constant that reflects the shape and the internal
structure of the matrix as well as the drug concentration and solubility.
4.9.4: Korsmeyer-peppas model which is log cumulative % drug release vs. log
time which is used to find out the mechanism of drug release (log % cumulative
release v/s log time)
Q=K2 tn.......... (13)
Where,
K2 is a constant incorporating the structural and geometric characteristics
of the matrix tablets
n is the release exponent indicating the drug release mechanism.

Methodology
Table 13: Different release mechanisms indicated ‘n’ value:
‘n’ Mechanism
0.5 Fickian Diffusion (Higuchi Matrix)
0.5<n<1 Anomalous Transport (First order)
1 Case-II Transport (Zero order release)
n>1 Super case-II Transport
This model is usually used to analyze the drug release when the mechanism
is not known or when more than one type of release process is involved.
4.11: Scanning electron microscopy:
Scanning electron microscopy is a useful analytical technique utilised to study

the surface morphology of coating membrane.
In scanning electron microscopy, coating membranes (varying in PEG-400

concentration) were obtained before and after complete dissolution of osmotic
tablets. Coating membranes were examined for their surface morphology by JEOL
JSM-5600 LV SEM camera (JEOL, Japan).
Coating membranes were dried in air and membrane samples were sputter
coated for 5-10 minutes with platinum by using auto fine coater ion sputter (JEOL-
JFC-1600, JEOL, Japan) and examined under scanning electron microscope.

Results
5. RESULTS
5.1: UV Spectrum of Ropinirole Hydrochloride in Different solvents:
The UV spectra of Ropinirole Hydrochloride in different solvents (0.1 N HCl,

Distilled water, Phosphate buffer pH 6.8, pH Phosphate buffer pH 7.4) showed that
the λmax of the drug was 249.5nm. This was similar to the reported value of 250nm.
Fig.- 2: UV spectrum of Ropinirole Hydrochloride in distilled water
5.2: Calibration curve of Ropinirole Hydrochloride:
The calibration curve of Ropinirole Hydrochloride in different solvents

(Distilled water, 0.1 N HCl, Phosphate buffer pH 6.8, Phosphate buffer pH 7.4) is
shown in fig.-3, 4, 5,and 6 respectively. The absorbance corresponding to the
concentration is shown in table 14. The R2 value was found to be 0.999 and equation
of the regression line was found to be y = 0.029 (0.1 N HCl and phosphate buffer pH
7.4) and y = 0.030 (Distilled water and Phosphate buffer pH 6.8).

Results
Table 14: Calibration curve of Ropinirole Hydrochloride in Different solvents

Concentration Absorbance (average ± SD)
µg/ml 0.1 N HCl Distilled Phosphate phosphate
water buffer buffer
pH 6.8 pH 7.4
0 0.000±0.000 0.000±0.000 0.000±0.000 0.000±0.000
2 0.057±0.005 0.057±0.011 0.063±0.005 0.060±0.002
4 0.115±0.016 0.121±0.009 0.124±0.004 0.119±0.001
6 0.181±0.027 0.185±0.008 0.186±0.002 0.179±0.003
8 0.237±0.024 0.248±0.009 0.250±0.002 0.238±0.005
10 0.289±0.028 0.307±0.009 0.305±0.005 0.295±0.001
0.35
Slope 0.030
0.3
0.25 R2 0.999
Absorbance
0.2
0.15
0.1
0.05
0
0 2 4 6 8 10 12
CONCENTRATION (µg/ml)
Fig.- 3: Calibration curve of Ropinirole Hydrochloride in distilled water
0.35 Slope 0.029

0.3
0.25 R² 0.999
Absorbance
0.2
0.15
0.1
0.05
0
0 2 4 6 8 10 12
concentration ( µg/ml)
Fig.- 4: Calibration curve of Ropinirole Hydrochloride in 0.1 N HCl

Results
0.35 Slope 0.030

0.3
Absorbance 0.25 R² 0.999
0.2
0.15
0.1
0.05
0
0 2 4 6 8 10 12
Fig.- 5: Calibration curve of Ropinirole Hydrochloride in

pH 6.8 phosphate buffer
0.35 Slope 0.029

0.3
R² 0.999
0.25
Absorbance
0.2
0.15
0.1
0.05
0
0 2 4 6 8 10 12
Fig.- 6: Calibration curve of Ropinirole Hydrochloride in

pH 7.4 phosphate buffer

Results
5.3: Drug-Excipient interaction study:
5.3.1: Fourier Transform Infra Red (FTIR) spectroscopy:
The IR spectra of drug, physical mixture of drug with excipients and drug in tablet
were form taken initially and after one month at 40⁰C and 75% RH are shown in
figure 8,9,10, 11 respectively. The characteristic peaks are compiled in table 15, 16
respectively.
Fig.- 7: Structure of ropinirole hydrochloride
Fig. - 8: IR spectrum of Ropinirole hydrochloride

Results
Fig. - 9: IR spectrum of Ropinirole hydrochloride with physical mixture
Table 15: Comparison of the characteristic IR peaks corresponding to the

functional groups in Ropinirole hydrochloride with that of the physical
mixtures.
Corresponding Literature value. Characteristic Characteristic

peaks of peaks of
functional groups (wave number
Ropinirole Ropinirole
cm-1) hydrochloride. hydrochloride
(wave number with physical
cm-1) mixture.
(wave number
cm-1)
(A) (B)
NH 3300 - 3450 3414.35 3447.38
= C-H 3000 – 3200 3075.9 3075.9
-C-H 2982 - 2862 2970 2918.73
C-C 1600 1604 1604
C=C 1400 1461.7 1455.03
C=O 1600 - 1900 1716.34 1624.75
C-N 1200 1244.83 1216.86

Results
Fig. - 10: IR spectrum of initial Ropinirole hydrochloride tablet
Fig. - 11: IR spectrum of Ropinirole hydrochloride tablet in humidity chamber

at 40ºc and 75% RH for one month

Results
Table 16: Comparison of the characteristic IR peaks corresponding to the

functional groups in formulation of Ropinirole hydrochloride osmotic tablets
Corresponding Literature value. Characteristic Characteristic

peaks of peaks Ropinirole
functional groups (wave number
Ropinirole hydrochloride
cm-1) hydrochloride in osmotic tablet at
osmotic tablet. 40ºC/75 % RH
(wave number (wave number
cm-1) cm-1) Humidity
chamber
[Initial] [Humidity
chamber]
NH 3300 - 3450 Merged Merged
= C-H 3000 – 3200 Merged Merged
-C-H 2982 - 2862 2910.06 2906
C-C 1600 1671.98 1674.87
C=C 1400 1430.92 1430
C-N 1200 1285.32 1283.39
4.3.2: Differential scanning calorimetry:
Fig. - 12: DSC thermogram of Ropinirole hydrochloride

Results
Fig. - 13: DSC thermogram of Hydroxypropylmethylcellulose
Fig. - 14: DSC thermogram of Microcrystalline-cellulose

Results
Fig. - 15: DSC thermogram of Sodium chloride
Fig. - 16: DSC thermogram of Magnesium stearate

Results
Fig. - 17: DSC thermogram of PVP K30
Fig. - 18: DSC thermogram of Cellulose acetate

Results
Fig. - 19: DSC thermogram of Ropinirole hydrochloride tablets
5.4: Dose calculation for controlled release osmotic tablets of Ropinirole:
5.4.1: Practical Dose calculation of Ropinirole:
The practically calculated dose of ropinirole for formulating release osmotic

tablets was found to be 3 mg. (calculated as per eq1).
5.4.2: Theoretical drug release calculation of Ropinirole:
As per the calculations, the controlled release tablets of ropinirole should

release 0.1155 mg (3.85%) of drug of after 1 hour and subsequently release of
0.1602mg (5.34%) every hour upto 18 hours.

Results
5.5: Evaluation of controlled release osmotic tablet:

 Precompression parameters.
 Post compression parameters.
5.5.1: Precompression parameters:
The granules were evaluated for bulk density, tapped density, Carr’s
consolidation index, Hausner’s ratio and angle of repose and the results are
shown in table 18.
Table 17: Precompression parameters of formulations F4 – F7
Formulations F4 F5 F6 F7
Bulk density* 0.230 0.222 0.225 0.219

(gm/cm3) ± ± ± ±
0.005 0.003 0.001 0.005
Tapped density* 0.262 0.256 0.259 0.252
(gm/cm3) ± ± ± ±
0.009 0.003 0.004 0.009
Carr’s index 12.21 13.28 13.12 13.09

(%)
Hausner’s ratio 1.13 1.15 1.15 1.15
Angle of repose* 20.28 23.61 24.69 22.58
(degrees) ± ± ± ±
0.040 0.025 0.029 0.027
Co -efficient of 0.369 0.437 0.459 0.416
friction* ± ± ± ±
0.007 0.004 0.007 0.001
*Average ± SD

Results
5.5.2: Post compression parameters:
The Post compression parameters of the tablets such as thickness of the tablets,
hardness, and % friability of different batches were determined and results are
shown in the table 19.
Table 18: Post compression parameters of formulations F4 – F7

Formulations F4 F5 F6 F7
Thickness* 4.5±0.14 4.0±0.03 4.5±0.09 4.5±0.07
(mm)
Hardness* 3.50±0.00 4.5±0.00 4.5±0.00 4.0±0.00
(kg/cm2)
% friability 0.09 0.03 0.06 0.04
Drug content 94.33% 99.66% 98.33% 99%
*Average ± SD

Results
5.6: In-vitro dissolution study:
The in-vitro dissolution data for formulations F4 and F5 were obtained and are
reported table 19.
Table 19: In-vitro Dissolution data for formulations F4-F5

Time(hr) F4 F5
0 0.00±0.00 0.00±0.00
1 10.91±3.04 4.72±1.60
2 11.7±1.68 6.76±1.72
3 21.42±2.73 10.78±1.47
4 27.3±1.56 15.99±1.39
5 33.58±0.22 18.52±3.38
6 35.94±1.86 22.49±2.72
7 40.64±2.83 25.14±2.89
8 41.4±3.49 33.67±0.45
9 45.9±4.15 40.69±0.90
10 49.89±3.01 51.45±4.51
11 56.25±3.06 55.45±4.42
12 63.29±0.01 60.38±4.67
13 63.55±1.36 67.04±1.93
14 66.67±0.13 69.92±2.10
15 68.11±4.35 73.11±1.42
16 - 79.11±2.28
17 - 82.99±1.31
18 - 86.08±2.65
Average of 3 trials ± SD

Results
F4 6.8 P. buffer F5 6.8 p. buffer

R² 0.9495 0.9826
100
80
60
% CR
40
20
0
0 5 10 15 20
Time in hour
Fig. - 20: In vitro drug release profile of formulations F4 and F5

Results
5.7: Characterisation of final (F5) formulation:
5.7.1: Effect of different dissolution media on In-vitro drug release profile of F5:
Table 21: Dissolution data of F5 in different dissolution media

Time(hr) phosphate 0.1 N HCl Distilled phosphate
buffer Water buffer
pH 6.8 pH 7.4
0 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00
1 4.72±1.60 5.74±2.19 2.5±0.27 14.93±4.15
2 6.76±1.72 7.58±2.49 4.49±0.42 15.23±2.75
3 10.78±1.47 11.47±3.23 7.36±0.32 18.96±3.28
4 15.99±1.39 14.56±4.16 17.78±1.51 22.5±2.20
5 18.52±3.38 22.03±2.78 18.96±0.82 28.1±2.75
6 22.49±2.72 29.64±4.51 23.49±0.28 30.93±2.56
7 25.14±2.89 37.68±4.59 30.22±1.77 34.10±2.38
8 33.67±0.45 45.01±4.91 34.88±1.72 42.2±4.26
9 40.69±0.90 49.3±4.52 43.76±1.99 45.0±1.81
10 51.45±4.51 52.52±5.07 46.83±2.21 48.1±2.05
11 55.45±4.42 54.93±4.16 49.14±2.13 52.43±0.40
12 60.38±4.67 58.48±4.56 52.44±1.27 59.4±1.32
13 67.04±1.93 64.7±4.24 57.88±3.58 61.9±0.86
14 69.92±2.10 69.29±4.19 60.88±1.61 68.43±2.65
15 73.11±1.42 74.25±3.67 64.59±2.83 71.93±2.28
16 79.11±2.28 79.85±2.64 70.13±0.96 77.2±1.90
17 82.99±1.31 83.53±1.48 76.81±0.95 81.1±1.95
18 86.08±2.65 88.11±1.75 83.13± 85.96±2.13

Results
F5 0.1 N HCl F5 7.4 P.Buffer F5 distilled water F5 6.8 p.buffer

R² 0.9916 0.9825 0.9903 0.9826
100
80
60
% CR
40
20
0
0 5 10 15 20
Time in hour
Fig. - 21: In vitro drug release profile of F5 in different dissolution media

Results
5.7.2: Effect of rpm on In-vitro drug release profile of F5:
Table 21: In-vitro Dissolution data of F5 at different rpm

Time(hr) 50 RPM 75 RPM 100 RPM
0 0.00±0.00 0.00±0.00 0.00±0.00

1 4.72±1.60 6.66±0.64 7.22±1.21
2 6.76±1.72 7.63±0,57 9.31±2.10
3 10.78±1.47 12.78±1.68 13.1±2.33
4 15.99±1.39 13.03±1.59 18.36±3.93
5 18.52±3.38 18.26±0.489 22.88±4.29
6 22.49±2.72 22.24±2.36 31.93±5.02
7 25.14±2.89 30.99±2.11 35.59±4.82
8 33.67±0.45 36.31±2.84 40.99±5.91
9 40.69±0.90 42.54±4.44 43.7±4.14
10 51.45±4.51 50.56±4.78 51.73±3.96
11 55.45±4.42 54.5±1.99 55.73±3.90
12 60.38±4.67 57.26±2.34 62.86±4.19
13 67.04±1.93 63.80±4.27 65.66±3.73
14 69.92±2.10 66.53±2.65 70.16±4.89
15 73.11±1.42 70.74±1.80 75.56±3.14
16 79.11±2.28 75.74±1.48 79.09±1.78
17 82.99±1.31 80.46±1.44 83.51±1.65
18 86.08±2.65 87.03±0.96 86.88±0.83

Results
75 RPM 100 RPM 50 RPM
R² 0.992 0.9966 0.9826
100
80
60
% CR
40
20
0
0 5 10 15 20
Time in hour
Fig. - 22: In vitro drug release profile of F5 at different rpm

Results
5.7.3: Effect of different osmogents on In-vitro drug release:
Table 22: In-vitro drug release of formulation F5 F6 and F7 containing different

osmogents
osmogents NaCl Dextrose KCl
Time(hr) F5 F6 F7
0 0.00±0.00 0.00±0.00 0.00±0.00

1 4.72±1.60 5.27±0.57 5.27±0.64
2 6.76±1.72 5.93±0.28 7.88±0.85
3 10.78±1.47 6.61±0.17 8.59±1.14
4 15.99±1.39 8.4±0.15 10.98±2.08
5 18.52±3.38 9.67±0.41 14.24±3.79
6 22.49±2.72 11.24±0.41 18.41±4.06
7 25.14±2.89 13.96±0.69 20.42±1.72
8 33.67±0.45 17.55±0.49 27.19±3.11
9 40.69±0.90 21.49±0.33 32.35±2.88
10 51.45±4.51 28.83±2.25 39.42±2.17
11 55.45±4.42 34.09±2.39 45.15±0.99
12 60.38±4.67 41.22±3.78 49.04±2.60
13 67.04±1.93 44.66±3.48 54.93±2.94
14 69.92±2.10 45.47±1.17 56.76±2.66
15 73.11±1.42 49.62±1.78 64.99±4.27
16 79.11±2.28 56.34±2.34 67.54±3.28
17 82.99±1.31 58.73±1.28 72.89±4.02
18 86.08±2.65 63.92±1.17 74.71±2.16

Results
NaCl KCl Dextrose

R² 0.9826 0.9759 0.944
100
80
60
% CR
40
20
0
0 5 10 15 20
Time in hour
Fig. - 23: Effect of different osmogents on in- vitro drug release profile

Results
5.7.4: Effect of dissolution media containing osmotic agents on In-vitro drug

release
Table 23: Effect of dissolution media containing osmotic agents

on In-vitro drug release
Time(hr) phosphate buffer phosphate buffer

pH 6.8 pH 6.8 +
sodium chloride
0 0.00±0.00 0.00±0.00
1 4.72±1.60 13.58±2.70
2 6.76±1.72 15.9±3.27
3 10.78±1.47 20.8±0.78
4 15.99±1.39 27.23±0.32
5 18.52±3.38 22.43±8.86
6 22.49±2.72 25.27±8.25
7 25.14±2.89 27.12±6.26
8 33.67±0.45 28.37±3.03
9 40.69±0.90 32.63±1.66
10 51.45±4.51 37.86±2.54
11 55.45±4.42 42.3±1.62
12 60.38±4.67 46.83±1.53
13 67.04±1.93 42.53±5.43
14 69.92±2.10 44.32±3.55
15 73.11±1.42 45.43±1.43
16 79.11±2.28 46.95±1.78
17 82.99±1.31 56.32±3.38
18 86.08±2.65 62.74±3.96

Results
100
NaCl c.p.o.m.
Stagnant
80 Drug
stagnant Drug layer
release release
60
40
20
0
0 5 Time 10 15 20
Fig. - 24: Effect of dissolution media containing osmotic agents


Results
5.7.5: Effect of mechanical drill and dense coat on in- vitro drug release profile:
Table 24: Comparison of controlled porosity osmotic membrane,

mechanically drill and dense coat
Time(hr) Controlled porosity Mechanically drill Dense coat

osmotic membrane
0 0.00±0.00 0.00±0.00 0.00±0.00
1 4.72±1.60 3.05±0.51 2.5±0.27
2 6.76±1.72 4.56±0.14 3.77±0.45
3 10.78±1.47 6.8±0.55 4.49±0.31
4 15.99±1.39 7.77±1.55 5.06±0.71
5 18.52±3.38 9.05±0/90 7.36±0.38
6 22.49±2.72 11.23±1.50 8.9±0.72
7 25.14±2.89 13.04±1.58 11.2±1.07
8 33.67±0.45 14.56±1.02 12.03±0.54
9 40.69±0.90 16.48±1.20
10 51.45±4.51 17.20±1.54
11 55.45±4.42 18.96±1.93
12 60.38±4.67 20.53±1.54
13 67.04±1.93
14 69.92±2.10
15 73.11±1.42
16 79.11±2.28
17 82.99±1.31
18 86.08±2.65

Results
Mechanical drill Dense coat c.p.o.p
Time 12 8 18
% CR 20.53 12.03 86.08
100
80
60
% CR
40
20
0
0 5 10 15 20
Time in hour
Fig.25 Effect of dissolution media containing osmotic agents


Results
5.8: Data treatment of In vitro drug release profile of F5 with different models:
The kinetic treatment was applied to the drug release from the final formulation (F5)
and the results are reported as follows:
5.8.1: First order:
Table 25: First order drug release Data

Time %CR (F5)
0 0.00±0.00
1 1.97±0.00
2 1.96±0.05
3 1.95±0.01
4 1.92±000
5 1.91±0.01
6 1.88±0.01
7 1.87±0.00
8 1.82±0.05
9 1.77±0.01
10 1.68±0.03
11 1.64±0.04
12 1.59±0.04
13 1.51±0.02
14 1.47±0.03
15 1.42±0.02
16 1.31±0.04
17 1.23±0.02
18 1.14±0.07

Results
First order curve
2.5 R² 0.9450
2
log % drug remained
1.5
0.5
0
0 5 10 15 20
Time
Fig.- 26 First order plot for drug release from F5

Results
5.8.1: Higuchi Plot:

Table 26: Higuchi drug release data
√Time %CR (F5)
0 0±0.00
1 4.72±1.60
1.41 6.76±1.72
1.73 10.78±1.47
2 15.99±1.39
2.23 18.52±3.38
2.44 22.49±2.72
2.64 25.14±2.89
2.83 33.67±0.45
3 40.69±0.90
3.16 51.45±4.51
3.31 55.45±4.42
3.46 60.38±4.67
3.60 67.04±1.93
3.74 69.92±2.10
3.87 73.11±1.42
4 79.11±2.28
4.12 82.99±1.31
4.24 86.08±2.65

Results
Higuchi plot
100
80
R² 0.7955
60
40
20
0
0 1 2 3 4 5
√ Time
Fig. 27: Higuchi plot for drug release from F5

Results
5.8.2: Korsmeyer plot:
Table 27: Korsmeyer drug release data

Log time Log %CR (F5)
0 0.00±0.00
0 0.67±0.11
0.301 0.82±0.09
0.477 1.03±0.05
0.602 1.2±0.04
0.648 1.26±0.07
0.778 1.35±0.04
0.845 1.4±0.04
0.903 1.52±0.00
0.954 1.6±0.01
1 1.71±0.04
1.041 1.74±0.03
1.079 1.78±0.04
1.113 1.82±0.01
1.146 1.84±0.01
1.176 1.86±0.01
1.204 1.89±0.01
1.23 1.91±0.00
1.25 1.93±0.01

Results
Korsmeyer
2.5
R² 0.9477
2
Log %CR
1.5
0.5
0
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Log time
Fig. 28: Korsmeyer plot for drug release from F5
Table 28: Dissolution data treatment of F5 in various models

Model R2
Zero order 0.9825
Higuchi 0.7955
Korsmeyer 0.9477
First order 0.94

Results
5.9: Scanning electron microscopy:
5.9.1: Coat before dissolution:
Fig. 29: Scanning electron microscopy of before dissolution coat
5.9.2: Coat after dissolution:
Fig. 30: Scanning electron microscopy of before dissolution coat

Discussion
DISCUSSION
Ropinirole is a non-ergoline dopamine D2 receptor agonist (indole

derivative) which has short half life of 6 hrs. It is approved in numerous countries
for its use in the management of Parkinson's disease, alone or as a combination
therapy.
The aim of present research work was to design and develop once a daily
oral osmotic drug delivery system of ropinirole to improve patient compliance and
thereby therapeutic effectiveness.
When ropinirole hydrochloride was scanned using double beam UV

spectrophotometer at a concentration of 1mg/ml using distilled water as a blank, the
spectra showed the peak of maximum absorbance at 249.5 nm against the reported
value of 250.0 nm. The calibration curve of ropinirole hydrochloride in distilled
water over a concentration range of 2 – 10 µg/ml was found to be linear with the R2
value of 0.999 and a slope value of 0.030. Similarly, calibration curve was also
constructed in 0.1 N HCl, pH 6.8 phosphate buffer and pH 7.4 phosphate buffer.
When the IR spectra of the drug was compared with that of the physical
mixture of the drug and excipients, it was found that the characteristic peaks
appeared at almost same wave number indicating absence of interaction between
drug and excipients. The physical mixture was compressed into tablets and kept at
40º C and 75% RH for one month. When the IR spectra of the sample was
compared with pure drug it was found that the characteristic peak of -NH stretching
and –CH stretching was merged. This can be attributed due to the presence of
moisture from sodium chloride. However, this does not indicate any interaction.
The DSC graph of pure drug showed the characteristic endothermic peak at
246.83ºC which corresponds to the melting point of the pure drug. Distinct peak for
drug is also observed in DSC thermograph of mixture of drug with excipients.
These results indicate the compatibility of the drug with the selected excipients.
The oral osmotic system of ropinirole was designed to release the drug
through a membrane containing pore forming agents. The coating solution

Discussion
comprised of 2% cellulose acetate along with PEG 400 as pore forming agent in the
concentration of 20% w/w of the polymer.
Initially the core tablets were prepared by direct compression method (F1-F3)
using HPMC K100/K4M as rate retarding polymers and sodium chloride as
osmotic agent.
After coating, these tablets were found to disintegrate within a short period of
3 hrs indicating the lack of sufficient mechanical strength to withstand the
dissolution for an extended period of time. Hence it was decided to adopt wet
granulation technique to improve the mechanical strength of the tablets by addition
of binders. Formulations F4 and F5 were prepared by wet granulation method, using
5% PVP K 30 as the binder and coated with polymeric solution of cellulose acetate.
The in-vitro dissolution profile of F4 containing 40% w/w HPMC K4M as

polymer, showed a cumulative release of 68% upto 15 hrs. In order to prolong the
release still further, it was decided to reduce the amount of HPMC K4M.
Formulation F5 was prepared using 30% HPMC K4M as a rate controlling

polymer and 2.8% w/w of sodium chloride. The blend exhibited good flow
properties and compressibility as indicated in table 18. The prepared tablets were
sufficiently hard (4.5 kg/cm2) and showed acceptable friability as given in table 19.
The in-vitro dissolution profile of F5 indicated that the drug release was
prolonged upto 18 hrs. The target release profile could be obtained with
formulation F5, which gave a release of 86.08% after 18 hours.
The effect of dissolution media and agitation rates on the drug release was
evaluated. It was found that the in-vitro dissolution profile of final formulation F5 at
different agitation rates (50, 75,100) and in different dissolution media (0.1 N HCl,
pH 6.8 phosphate buffer, pH 7.4 phosphate buffer) was almost similar (table 21 and
22). The results indicate that the drug release from the formulated osmotic tablets
was independent of the agitation and pH of the dissolution media.
The effect of different osmogents on the drug release was also studied.
Formulations F6 and F7 were prepared with 2.8% w/w of dextrose and potassium

Discussion
chloride respectively. In-vitro release studies revealed that the drug release from the
tablets were in the order F5 > F7 >F6 (Fig No. 23). This could be attributed to the
difference in osmotic pressure of the osmogents used [NaCl (356 atm) > KCl
(245atm) > Dextrose (82atm)]. Due to high osmotic pressure of sodium chloride
compared to other osmotic agents, the formulation F5 showed an extended release
compared to formulations containing KCl (F7) and dextrose (F6) as indicated in
table 23.
The effect of addition of an osmogent in the dissolution media was

investigated. In-vitro release of formulation F5 was carried out in 250 ml phosphate
buffer pH 6.8 containing 250 mg of sodium chloride. The release from the tablet
was found to be reduced (62.74% after 18 hours) compared to that obtained in
phosphate buffer pH 6.8 without NaCl (Fig. 24). As the environment (Osmotic
Pressure) was similar on both the sides of the tablet, flow of media into and
subsequently the dissolved drug from the tablet was less which resulted in a lesser
release.
To study the effect of different coating membranes, formulation F5 was coated

with dense coat comprising of cellulose acetate without a pore forming agent. As an
alternative to controlled porosity coating, the dense coated tablets were also
mechanically drilled using a needle. In-vitro dissolution data showed that drug
release from dense coat and mechanically drilled osmotic tablet was very low as
compared to controlled porosity membrane which released drug for prolonged
period of time in controlled manner as indicated in table 25. These results indicate
that controlled porosity is essential to achieve a prolonged and controlled release of
the drug from an osmotic system.
In-vitro release data of final batch F5 was fitted with various

mathematical models like zero order, Higuchi, Korsmeyer and first order. It was
found that the drug release followed zero order rate kinetics (R2-0.9825) as
indicated in table-29. This confirms that the drug release from the formulated
osmotic drug delivery system was controlled by osmotic pressure and not by
diffusion and was independent of pH, agitation rate and environmental factors.

Conclusion
CONCLUSION
Once a day oral osmotic tablet for highly water soluble “ROPINIROLE” was
successfully developed which could deliver the drug for prolonged period of time,
The osmotic tablets of ropinirole formulated using HPMC K4M as swellable
polymer and sodium chloride as osmotic agent, coated with controlled porosity
membrane coat gave the desired release up to18 hrs. Controlled porosity coating
was helpful in controlling the release of the drug for the prolonged period. The
developed ONCE A DAY ORAL OSMOTIC DRUG DELIVERY SYSTEM OF
ROPINIROLE formulation to help in reducing the dosing frequency and improve
the patient compliance, as compared to the conventional tablets. These tablets were
prepared using a simple technique which could be adapted to large scale
production.

Summary
SUMMARY
The aim of present research work was to develop once a daily formulation of
osmotic drug delivery system of ropinirole to improved patient compliance by
reducing frequency of the dose administration as compared to marketed
conventional tablets and thereby therapeutic effectiveness.
The IR spectra and differential scanning calorimetry of the drug was

compared with that of the physical mixture of the drug and excipients, it indicated
the absence of interaction between them.
The osmotic tablets were formulated by wet granulation techniques using a

swellable polymer and osmogents in the core and coated with cellulose acetate
solution containing a pore forming agents.
The effect of dissolution media (0.1 N HCl, water, pH 6.8 phosphate buffer,
pH 7.5 phosphate buffer) and agitation rate (50, 75, 100) on the drug release was
also studied. The release rate was not affected by different dissolution media and
agitation rate. The effect of different osmogen on the drug release was also studied.
Due to high osmotic pressure of sodium chloride compared to other osmotic agents,
the tablets showed faster release.
The granules were evaluated for bulk density, tapped density, Carr’s index,
Hausner’s ratio and angle of repose. The prepared tablets were evaluated for
thickness, hardness, percent friability and drug content. All the results obtained
were found to be satisfactory. The final formulation containing 30% HPMC and
2.8% NaCl gave a desired controlled drug release for a period of 18 hour. In-vitro
data obtained from dissolution studies carried out in different dissolution media
containing osmotic agent showed that drug was released by osmotic pressure
generated inside tablets and not by diffusion.
In-vitro release profiles of final batch F5 was compared with osmotic tablet
with mechanically drilled orifice and osmotic tablet coated with dense coat of
cellulose acetate without pore forming agent. Dissolution data showed that drug
from dense coat and mechanically drilled osmotic tablet was very low as compared

Summary
to controlled porosity membrane which released drug for prolonged period of time
in controlled manner.
Water soluble poreforming agent present in coating membrane leaches out

after coming in contact with dissolution media forming microporous membrane.
Formation of pores in coating membrane was confirmed by surface morphology
studies performed by scanning electron microscopy.
In-vitro drug release data of selected optimized formulation was fitted with
various mathematical models to study the release kinetics. From the data it was
confirmed that the drug release followed zero order rate kinetics diffusion playing a
minor role. The drug release was increased linearity with increase in concentration
of osmotic agents.

Bibilograph
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Design and Development of Once A Day Ora

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Design and Development of Once a Day Oral Osmotic

Drug Delivery System of Ropinirole

Dissertation submitted to the

Department of Pharmaceutical Technology,

DECLARATION BY THE CANDIDATE

“Design and development of Once A Day Oral Osmotic Drug

(A constituent unit of KLE Academy of Higher Education and Research

CERTIFICATE BY THE GUIDE

“Design and development of Once A Day Oral Osmotic Drug

is a bonafide and genuine research work carried out by Pansuriya Purvang C.

in partial fulfilment of the requirements for the degree of Master of

Date: Mrs. Uma A. Patil

(A constituent unit of KLE Academy of Higher Education and Research

ENDORSEMENT BY THE HEAD OF THE DEPARTMENT AND

“Design and development of Once A Day Oral Osmotic Drug

is a bonafide and genuine research work carried out by Pansuriya Purvang C.

under the guidance of Mrs. Uma A. Patil, Asst. Professor, KLE

University’s College of Pharmacy, Bangalore.

DECLARATION BY THE CANDIDATE

I hereby declare that the KLE Academy of Higher Education and

Research – Deemed University have the rights to preserve, use and

disseminate this dissertation/thesis in print or electronic format for

academic / research purpose.

© KLE Academy of Higher Education and Research-Deemed University

Life is a chemistry, just dilute your sorrows,

evaporate your worries, filter ur mistake,

boil your ego and you will get the crystal of

My guide. My philosopher. It is just for the sake of differentiating that I

How could I forget to show my poignant gratification to Dr. Rajeshri Dhurke

Nitin Dobariya. My brother. He was as disquiet as me and finally provided me

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY, KLEUCP, BANGLORE. 1

Whenever it comes to pen down the names I want to acknowledge, I would

Friend is a medicine for any kind of wound

There is no medicine found in the world for would given by

Place:- Bangalore Pansuriya Purvangkumar C.

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY, KLEUCP, BANGLORE. 2

Sr. No. Contents Page No.

 % CR: Percentage cumulative release

 API: Active pharmaceutical ingredients

 COMT: Catechol-o-methyl transferase

 CPOP: Controlled porosity osmotic pump

 CPOP: Controlled porosity osmotic pump

 DSC: Differential Scanning Calorimetry

 EOP: Elementary osmotic pump

 FTIR: Fourier Transform Infrared

 HCl: Hydrochloric acid

 HPMC: Hydroxy propyl methyl cellulose

 IVIVC: In vivo- in vitro correlation

 JP: Japanese Pharmacopoeia

 KCl: Potassium chloride

 L-OROS: Liquid oral release osmotic system

 MCC: Microcrystalline cellulose

 MOB: Monoamine oxidase

 NaCl: Sodium chloride

 OROS-CT : Oral release osmotic system colon targeting

 PD: Parkinson disease

 PEG: Polyethylene glycol

 PEO: Poly ethylene oxide

 Ph Eur: Pharmacopoeia of Europe

 PVP: Poly vinyl pyrrolidone

 SLS: sodium lauryl sulphate

 SOTS: Sandwiched osmotic tablets

 USP: United State Pharmacopoeia