Divalproex Sodium

FORMULATION DEVOLOPMENT AND EVALUATION OF
DIVALPROEX SODIUM EXTENDED RELEASE TABLET

BY
V V GANESH P
Dissertation submitted to
KLE Academy of Higher Education & Research Deemed University, Belgaum,
Karnataka
In partial fulfilment of the requirements for the degree of

MASTER OF PHARMACY
IN
PHARMACEUTICS

Under the guidance of
Dr. B.G.DESAI

Department of Pharmaceutics
KLE Universitys College of Pharmacy, Bangalore- 5660010
2013

KLE ACADEMY OF HIGHER EDUCATION AND RESEARCH
- DEEMED UNIVERSITY, BELGAUM, KARNATAKA

DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation entitled

is a bonafide and genuine research work carried out by me under the guidance
of Dr. B.G.DESAI Professor, Department of Pharmaceutics, KLE
Universitys College of Pharmacy, Bangalore.

Date:
Place: Bangalore V V GANESH P

KLE UNIVERSITYS COLLEGE OF PHARMACY,
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
DIVALPROEX EXTENDED RELEASE TABLET

is a bonafide research work done by V V GANESH P under my
supervision and guidance, in partial fulfilment of the requirement for
the award of degree of MASTER OF PHARMACY IN PHARMACEUTICS.

Date:
Place: Bangalore
Dr. B.G.DESAI
Professor
KLE Universitys
College of Pharmacy
Rajajinagar, Bangalore-560010

BANGALORE-560010
(A constituent unit of KLE Academy of Higher Education and Research
Deemed University)

ENDORSEMENT BY THE HEAD OF THE DEPARTMENT


is a bonafide and genuine research work carried out by V V GANESH P. under
the guidance of Dr. B.G.DESAI Professor, Department of Pharmaceutics,
KLE Universitys College of Pharmacy, Bangalore.

Date:
Place: Bangalore
Dr. H. N. SHIVAKUMAR
Professor & Head of Department
KLE Universitys
College of Pharmacy

BANGALORE-560010
(A constituent unit of KLE Academy of Higher Education and Research
Deemed University)

ENDORSEMENT BY THE HEAD OF THE INSTITUTION

is a bonafide and genuine research work carried out by V V GANESH P. under
the guidance of Dr. B.G.DESAI Professor, Department of Pharmaceutics,
KLE Universitys College of Pharmacy, Bangalore.

Date:
Place: Bangalore
Dr. B.G.DESAI
PRINCIPAL
KLE Universitys
College of Pharmacy
ACKNOWLDGEMENT

I have worked with a great number of people whose contribution in
assorted ways to the research and the making of the thesis deserved special
mention. It is a pleasure to convey my gratitude to them all in my humble
acknowledgment.

I would like to first express my gratitude & indebtedness, to my Parents
Lt. Mr. P VENU & Mrs. P VASUNDHARA, whose love and support made this
day possible in my life. There are no words, which can express my gratitude
towards my brother SUBHASH, my uncle & aunt Mr. P VENKATESWARAO &
Mrs. P LAKSHMI and also my sisters YAMIKA & RACHALA for their
constant support, immense care, faith in me and divine love towards me, which
made my dream come true.

I would like to record my gratitude to my gracious mentor Dr. B. G.
Desai, Guide and Principal, K.L.E. Universitys College of Pharmacy,
Bangalore, for his supervision, advice and guidance from the very early stage of
this research as well as giving me extraordinary experiences throughout the
work. Above all and the most needed, he provided me unflinching encouragement
and support in various ways. His truly scientist intuition has made him as a
constant oasis of ideas and passions in science, which exceptionally inspire and
enrich my growth as a student, a researcher and a scientist want to be. I am
indebted to him more than he knows.

I wish to express my sincere thanks, with a deep sense of gratitude to
Dr. H. N. Shivakumar, Dr. Uma A Patil, Mrs. Preeti G.B, Mrs. Anasuya
Patil. Department of Pharmaceutics, KLE Universitys College of Pharmacy,
Bangalore for their generous consideration and facilities that lead to successful
completion of my project.

To the non-teaching staff: Mr. Biradar, Mr. Suresh, Mr. Satish, Mr.
Reddy for their help and support.

I would like to express my sincere thanks and heartful gratitude to my
batchmates and friends Gopal, Sudheer, Kiran, Ankith, Nirbhay, Pradeep,
Shankar, Melvin Naresh, jagadish, Swathi, Anusha, Nazia, Sanchita,
Haritha, Uma, & Sruthi.
From the core of my heart, I express my special thanks to my friends
from other departments Sundeep, Subrahmanyam, Gopal, Nikhil, Bhargav,
Narendra, Swetha, Amrutha, Rohitha, Roopa and all others.

I would also like to thank my dynamic seniors Ayush, Naveen, Rahul,
Jaydeep, Amol, Jakson, Pradip, Srikant S, Narendra, Vamshi, Nagmanohar,
Anil, Khushboo, Shruthi, Usha , Mounika and Aparna and all others for their
kind co-operation during my research work. I am also thankful to all my juniors
for their support and kind co-operation.

I shall forever remain indebted to my Co-guide S. Godwin Kumar,
Scientist-I, APL Reasearch Centre, Aurobindo Pharma LTD, Hyderabad, allowing
me to carry out M.Pharm dissertation work within a well-established
organization along with their valuable guidance, keen interest, perennial
inspiration and everlasting encouragement. And my thanks to Mr. G.
Ravindranath, V. Sandeep Kumar, Subrahmanyam, Rahul, Anil, Arjun for
their valuable help and guidance during my research work.

Last.but not the least, I wish to express my gratitude towards God-
almighty, who gave me the strength and courage to fulfill my dream and has
showered upon me his choicest blessings.
Thankful I ever remain

V V GANESH P

IN MEMORY OF MY
D A D

You are my inspiration
ur son
LIST OF ABBREVIATIONS
API Active Pharmaceutical Ingredient
BBB Blood-Brain Barrier
CNS Central Nervous System
DDS Drug Delivery System
DR Delayed Release
% DR % Drug Release
EC Ethyl Celluose
ER Extended Release
EEG Electroencephalogram
GABA Gamma Aminobutyric Acid
GAD Glutamic Acid Decarboxylase
GAT-1 Gamma Aminobutyric Acid Transporter
HDPE High Density Polyethene
HPC Hydroxy Propyl Celluose
HPMC Hydroxy Propyl Methyl Celluose
HEC Hydroxy Ethyl Celluose
ICH International Conference of Harmonization
LDPE Low Density Polyethene
LOD Loss on Drying
NMDA N-Methyl D-Aspartate
SDS Sodium Dodecyl Sulphate
UV Ultra Violet
USP United States Pharmacoepia

TABLE OF CONTENTS

S.NO CONTENTS Pg NO.
1 ABSTRACT 1
2 INTRODUCTION 2
3 REVIEW OF LITERATURE 17
4 AIM AND OBJECTIVE 18
5 MATERIALS AND METHODS 19
6 RESULTS 33
7 DISCUSSION 53
8 CONCLUSION 56
9 SUMMARY 57
10 BIBLIOGRAPHY 59

LIST OF TABLES
Table No. Table
1.1 Physico-chemical properties of Divalproex Sodium
4.1 List of Materials used in Study
4.2 List of Equipments used in Study
4.3 Limits of Carrs Index
4.4 Limits of Hausners Ratio
4.5
Limits of Angle of Repose
4.6 Drug:Excipient Ratio for Compatibility Study
4.7
Parameters for Tablet Compression
4.8 Formulations for F
1
-F
8
4.9 Dissolution at Acid Stage
4.10
Dissolution at Buffer Stage
5.1 Data for Calibration Curve of Divalproex Sodium
5.2
Physico-Chemical Properties of Innovator Product
5.3 In vitro Drug Release Profile of Innovator Product
5.4 API Characterization
5.5 Drug: Excipient Ratio for Physical Compatibility Study
5.6 Drug: Excipient Ratio for Chemical Compatibility Study
5.7
Evaluation of F
1
5.8 In vitro Dissolution Data of F
1
5.9
Evaluation of F
2

2

5.11 Evaluation of F
3

3
4
4
5
5
6
6
7
7
8
8
5.23 Accelerated Stability Data of F
8

LIST OF FIGURES
Figure No. Figure
1.1 Types of Modified Release Tablet
1.2 Drug Release in Swellable Matrix System
1.3 Zones in Swellable Matrix System
1.4 Chemical Structure of Valproic acid
1.5 Chemical Structure of Divalproex Sodium
4.1 Innovator Brand Label
4.2 Schematic Representation of Manfacturing Process
5.1 Standard Graph of Divalproex Sodium
5.2 Innovator Drug Release Profile
5.3 X-Ray Powder Diffraction Study of Divalproex Sodium & Excipients
5.4 Comparative In vitro Drug Release Profile of F
1
with Innovator
2
with Innovator
3
with Innovator
4
with Innovator
5
with Innovator
6
with Innovator
7
with Innovator
8
with Innovator

DIVALPROEX SODIUM ER
ABSTRACT
1

DIVALPROEX SODIUM ER Page 1


ABSTRACT

The objective of present work is to develop a stable solid dosage form of extended
release tablets of divalproex sodium for the treatment of epilepsy, migraine, and bipolar
disorders. In present study divalproex sodium extended release tablets were prepared using
HPMC as polymer and eudragit NE 40D acts as binding agent and were prepared by wet
granulation technique. This formulation is a hydrophilic matrix formulation, where the drug
is released by diffusion and erosion. This formulation is likely to minimise the variation
between peak and trough plasma levels of valproate over a 24hr dosing period which follows
a zero-order release pattern thus producing essentially flat levels of valproate. This results in
significantly lower the incidence of side effects. This formulation is swelling controlled drug
release system in which drug is released by both diffusion and erosion.
In the preformulation study, the pure drug was evaluated for properties such as bulk
density, tapped density, Compressibility index and Hausners ratio. The results indicated that
the drug has poor flow property but passable (Compressibility index = 22.472% and
Hausners ratio = 1.292%).The drug excipient compatibility studies indicated that there was
no physical change in the drug when mixed with various excipients and subjected to
accelerated stress conditions (40
0
C/75%RH) upto 4weeks.
Formulations F1 - F8 were prepared by wet granulation technique and each
formulation is evaluated for drug release in comparison to innovator. In formulation F8 the
concentration of starch 1500 was increased to 5.65% and the drug concentration was kept to
53.27% all other concentration were kept same as that of F4. Initially high drug concentration
was observed but maintained all over the time period. The percentage drug release for this
formulation was maintained with innovator in close range. Hence, formulation F8 was
considered to be the optimized formulation in which the release profile was found to be
very close to that of innovator (%DR= 98).

INTRODUCTION
2


1. INTRODUCTION
1.1EPILEPSY:
Epilepsies are a group of disorders of CNS characterized by paroxysmal cerebral
dysrhythmia, manifesting as brief episodes (Seizures) of loss or disturbance of consciousness,
with or without characteristic body movements (Convulsions)
1
. Epileptic seizures result from
abnormal, excessive or hyper synchronous neuronal activity in the brain
2
. About 50 million
people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing
countries
3
. Epilepsy becomes more common as people age
4, 5
. Epilepsy is usually controlled,
but not cured, with medication. However, more than 30% of people with epilepsy do not have
seizure control even with the best available medications. Surgery may be considered in
difficult cases. Not all epilepsy syndromes are life long some forms are confined to
particular stages of childhood. Epilepsy should not be understood as a single disorder, but
rather as syndrome with vastly divergent symptoms, all involving episodic abnormal
electrical activity in the brain and numerous seizures
6, 7
.
1.1.1Causes:
The diagnosis of epilepsy usually requires that the seizures (rapid and uncontrolled
body movements due to sudden abnormal and excessive neuronal activity in brain) occur
spontaneously. Nevertheless, certain epilepsy syndromes require particular precipitants or
triggers for seizures to occur. These are termed reflex epilepsy. For example, patients with
primary reading epilepsy have seizures triggered by reading. Photosensitive epilepsy can be
limited to seizures triggered by flashing lights. Other precipitants can trigger an epileptic
seizure in patients who otherwise would be susceptible to spontaneous seizures. For example,
children with childhood absence epilepsy may be susceptible to hyperventilation. In fact,
flashing lights and hyperventilation are activating procedures used in clinical EEG to help
trigger seizures to aid diagnosis. Emotional stress, sleep deprivation, sleep itself, heat stress,
alcohol and febrile illness are examples of precipitants cited by patients with epilepsy.
Notably, the influence of various precipitants varies with the epilepsy syndrome
8
. Likewise,
the menstrual cycle in women with epilepsy can influence patterns of seizure recurrence.
Catamenial epilepsy is the term denoting seizures linked to the menstrual cycle
9
.
When investigating the causes of seizures, it is important to understand physiological
conditions that may predispose the individual to a seizure occurrence. Several clinical and
INTRODUCTION
3


experimental data have implicated the failure of bloodbrain barrier (BBB) function in
triggering chronic or acute seizures, some studies implicate the interactions between a
common blood protein albumin and astrocytes
10, 11
. These findings suggest that acute seizures
are a predictable consequence of disruption of the BBB by either artificial or inflammatory
mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB
are a significant mechanism of resistance to commonly used anti-epileptic drugs
12
.
1.2 TYPES OF EPILEPSY:
1, 13
The clinical classification of epilepsy defines two major categories, namely partial
and generalised seizures.
1.2.1 Generalised Seizures:

Generalised seizures involve the whole brain, including the reticular system, thus
producing abnormal electrical activity throughout both hemispheres. Immediate loss of
consciousness is characteristic of generalised seizures.
TONIC-CLONIC SEIZURES:
It is also called grand mal epilepsy. It is most common and lasts for 1-2 min. It
consists of an initial strong contraction of whole musculature, causing a rigid extensor spasm
and an involuntary cry. Respiration stops and defecation and salvation often occur. The
patient stays unconscious for few more minutes and then gradually recovers.
ABSENCE SEIZURES:
It is also called petit mal epilepsy or minor epilepsy. Absence seizures occur in
children and lasts about 1/2min. They are much less dramatic but may occur more frequently
than grand mal seizures. The patient abruptly ceases whatever he or she is doing and stares
vacantly for few seconds, with little or no motor disturbance. Patients are unaware of their
surroundings and recover abruptly with no after-effects.
ATONIC SEIZURES:
It is also called as akinetic epilepsy. Unconsciousness with relaxation of all muscles
due to excessive inhibitory discharges. Patient may fall.

INTRODUCTION
4


MYOCLONIC SEIZURES:
Momentary contractions of a muscle of a limb or whole body.
INFANTILE SPASMS (HYPSARRHYTHMIA):
Seen in infants. Probably not a form of epilepsy. Intermittent muscle spasm and
progressive mental deterioration. Diffuse changes in the interseizure EEG are noted.
1.2.2Partial seizures:
Partial seizures are those in which the discharge begins locally and often remains
localised. The symptoms depend on the brain region or the regions involved, and include
involuntary muscle contractions, abnormal sensory experiences or autonomic discharge, or
effects on mood and behaviour, often termed psychomotor epilepsy.
SIMPLE PARTIAL SEIZURES:
Lasts for 1 min. Often secondary. Convulsions are confined to a group of muscles or
localised sensory disturbance depending on the area of cortex involved in the seizure, without
loss of consciousness.
COMPLEX PARTIAL SEIZURES:
Attacks of bizarre and confused behaviour and purposeless movements, emotional
changes lasting 1-2 min along with impairment of consciousness. An aura often precedes.
The seizure focus is located in the temporal lobe.
1.3DRUG DELIVERY SYSTEM
14,15,16,17,18

The treatment of acute diseases or chronic illness has been achieved by delivery of
drugs to the patients for many years. These drug delivery systems include tablets, injectables,
suspensions, creams, ointments, liquids and aerosols. Today these conventional drug delivery
systems are widely used. The term drug delivery can be defined as techniques that are used
to get the therapeutic agents inside the human body. Another role of the delivery systems is to
allow the safe application of the drug. This includes that the drug in the formulation must be
chemically, physically and microbiologically stable. Side-effects of the drug and drug
interactions should be avoided or minimized by the use of suitable drug delivery systems.
The delivery systems also need to improve the patients compliance with the
pharmacotherapy by the development of convenient applications. For example, one can
INTRODUCTION
5


improve patient compliance by developing an oral dosage form where previously only
parenteral application was possible. Finally, the delivery system needs to be reliable and its
formulation needs to be technically feasible. This means the Pharmaceutical quality of the
delivery systems needs to be assured, drug release from the system needs to be reproducible
and the influence of the body on drug release should be minimized. (For example, food
effects after oral administration).
1.3.1 Conventional Drug Therapy
19,20,21,22

Conventional drug therapy requires periodic doses of therapeutic agents. These agents
are formulated to produce maximum stability, activity and bioavailability. For most drugs,
conventional drug delivery is effective, but some drugs which possess narrow therapeutic
window and which cause irritation to gastric mucosa require modified drug delivery system
to achieve desired therapeutic effect. These delivery systems have a number of advantages
over traditional systems such as improved efficiency, reduced toxicity and improved patient
convenience. The main goal of modified drug delivery systems is to improve the
effectiveness of drug therapies.
Conventional dosage forms are rapidly absorbed, with the ascending and descending
portions of the concentrations versus time curve reflecting primarily the rate of absorption
and elimination, respectively. Because of the rapid rate of absorption from conventional
dosage forms, drugs are usually administered more than once daily, with the frequency being
dependent on biological half-life (t) and duration of pharmacological effect. The time of
dosing may also be effected by therapeutic index of a drug.
Disadvantages of Conventional Drug Delivery Systems
23

In conventional oral drug delivery systems, there is little or no control over the release
of the drug and effective concentration at the target site.
The dosing pattern in conventional dosage forms results in constantly changing,
unpredictable and often sub-therapeutic plasma concentrations, leading to marked side
effects in some cases.
Conventional drug delivery system is not suitable for the drugs which cause irritation
to the gastric mucosa.
The rate and extent of absorption of drug from conventional formulations may vary
greatly, depending on the factors such as physicochemical properties of the drug,
INTRODUCTION
6


presence of excipients, various physiological factors such as the presence or absence
of food, pH of the gastrointestinal tract, gastrointestinal motility and so on.
1.3.2 MODIFIED DRUG DELIVERY SYSTEMS
24,25

Dosage forms can be designed to modify the release of the drug over a given time or
after the dosage form reaches the required location. Drug release only occurs sometime after
the administration or for a prolonged period of time or to a specific target in the body.
Modifications in drug release are often desirable to increase the stability, safety and efficacy
of the drug, to improve the therapeutic outcome of the drug treatment and/or to increase
patient compliance and convenience of administration.
Classification:
Modified Release dosage form may be classified as
Extended Release
Controlled Release
Sustained release
Delayed Release
1.3.3 Extended release Oral Drug Delivery Systems:
Extended Release oral DDS allows the drug to be released over prolonged time
periods. By extending the release profile of a drug, the frequency of dosing can be reduced.
Extended release can be achieved using sustained or controlled-release dosage forms.
Fig1.1: Types of Modified Release Tablet

MODIFIED-RELEASE TABLET
EXTENDED-RELEASE
TABLET
CONTROLLED
SUSTAINED
DELAYED-RELEASE
TABLET
INTRODUCTION
7


1.3.3.1 Controlled Release Oral Drug Delivery System:
Controlled Release Dosage form is generally accomplished by attempting to obtain
zero- order release from the dosage form which independent of the amount of drug in the
delivery system (i.e., a constant release rate). 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 thereby
increasing therapeutic value of the drug. Oral controlled release formulations are becoming
increasingly popular in the pharmaceutical industry because they improve likelihood of a
patient actually taking the medicine, thereby reducing the side effects and providing an
extended patient protection. Oral controlled drug delivery system can be classified as rate
programmed drug delivery system and stimuli-activated drug delivery system.
Classification of Rate-Controlled Drug Delivery System:-
Based on the techniques of drug delivery the controlled release drug delivery systems can be
classified as follows:
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.
o Slow dissolution rate of the drug,
o Slow dissolution rate of the reservoir membrane or matrix.
Diffusion controlled drug delivery system.
o Porous matrix controlled system,
o Porous membrane controlled system.
Erosion controlled drug delivery system.
o Surface erosion,
o Bulk erosion.
Combination of dissolution, diffusion and/or erosion controlled drug delivery system.
o Reservoir system,
o Matrix system,
o 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.
INTRODUCTION
8


Activation by the biological process:
Enzyme activated drug delivery system.
o Urea responsive drug delivery system,
o 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.
o pH dependent solubility system,
o pH dependent erosion/degradation system,
o pH dependent swelling system.
Ion activated drug delivery system.
Hydrolysis activated drug delivery system.
Chelation activated drug delivery system.

Activation by the physical process:
Electrically activated drug delivery system.
o Iontophoresis,
o Electroporation
Hydrodynamic pressure activated drug delivery system.
Mechanical force 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.
INTRODUCTION
9


1.3.3.2 Sustained Release Oral Drug Delivery System:
The term Sustained Release is constantly used to describe a pharmaceutical dosage
form formulated to retard the release of the therapeutic agent such that its appearance in the
systemic circulation is delayed and prolonged and its plasma profile is sustained in duration.
The onset of its pharmacological action is often delayed, on the duration of its therapeutic
effect is sustained.
1.3.4 Delayed Release
26, 27

A Delayed Release dosage form is designed to release the drug at a time other than
promptly after administration. Dosage forms can be designed to modify the release of the
drug over a given time or after the dosage form reaches the required location.
Delayed Release oral dosage forms can control where the drug is released, e.g. when
the dosage form reaches the small intestine (enteric-coated dosage forms) or the colon (colon-
specific dosage forms). Delayed Release systems release a bolus of the drug after a
predetermined time in a predetermined location, i.e. they do not release the drug immediately
after ingestion, for example enteric-coated tablets, pulsatile-release capsules.
The two types of delayed release systems are:

Intestinal Release System
Colonic Release System
Intestinal Release System: A drug may be enteric coated for intestinal release for
several known reasons such as to prevent gastric irritation, prevent destabilization in gastric
pH

etc.
Colonic Release System: Drugs are poorly absorbed through colon but may be
delivered to such a site for two reasons
Local action in the treatment of ulcerative colitis.
Systemic absorption of protein and peptide drugs.

The extended release once-a-day formulation is a hydrophilic matrix dosage form.
Drug delivery of current formulation is by the combination of diffusion,
dissolution and erosion.
INTRODUCTION
10


1.4 MATRIX SYSTEM:
Matrix tablets are the most extensively used solid dosage forms. They are prepared by
usually compressing a powder containing a drug or drugs with excipients. The goal of
controlled delivery systems are to reduce the frequency and/or to increase the effectiveness of
the drug localization at the target site, thereby reducing the dose required to provide uniform
drug delivery. The commonly used polymers for controlled release are hydroxy propyl
methyl cellulose (HPMC), hydroxy propyl cellulose (HPC), hydroxyl ethyl cellulose (HEC),
ethyl cellulose (EC), methylcellulose (MC), carboxy methylcellulose (CMC), polyvinyl
pyrrolidone (PVP) and polyethylene glycol (PEG).
These polymers, which swell in aqueous medium, are often used for the preparation
of controlled-release dosage forms. These are highlighted with the presence of a solvent
front, the potential for unlimited swelling, and the combined controlling mechanism of
diffusion and erosion as being the distinguishing feature of HM devices.

Advantages perceived for some hydrophilic matrix systems are:
Simplicity of formulation
High drug loading
Reduction in drug blood level fluctuations
Reduction in dosing frequency
Reduction in adverse side effects and
Reduction in health care costs i.e., economy
28
.

1.4.1 Mechanism of drug release from swellable matrix tablets:
Controlled drug release is based on diffusion through polymers, erosion of polymers
and special polymer characteristics such as osmotic and ion exchange properties. When a
glassy (or dry) polymer comes into contact with water or any other medium with which it is
thermodynamically compatible, the solvent penetrates into the free spaces on the surface
between the macromolecular chains. When enough solvent has entered into the matrix, the
glass transition temperature (Tg) of the polymer drops to the level of the experimental
temperature (which is usually 37
0
C) except for poly (ethy1ene oxide) whose Tg is
approximately 60
0
C. Therefore polymers with a Tg greater than 37
0
C in their dry (glassy)
state can be used to prepare swelling controlled-release dosage forms. The presence of
solvent in the glassy polymer causes stresses, which are then accommodated by an increase in
INTRODUCTION
11


the radius of gyration and end-to-end distance of the polymer molecules, i.e., the polymer
chains get solvated. The increase in the radius of gyration of the polymer molecules is seen
macroscopically as "swelling of the matrix". The solvent molecules move into the glassy
polymer matrix with a well-defined front at a particular velocity and simultaneously, the
thickness of the swollen or rubbery region increases with time in the opposite direction. The
time taken for the increase in radius of gyration of the polymer molecules, which is a
relational phenomenon, is a characteristic for that particular polymer/solvent system
29
.

A matrix tablet during swelling is an aggregate mass of water-swollen polymer, drug,
and excipients experiencing various degrees of hydration or solution as illustrated in Figure
1.1. The tablet contains regions with solid content varying from 0 to 100%. In the area near
100% solids, the gel is a wetted mass of powders. As water content of the wetted powder
mass increases, the polymer becomes hydrated and develops into a gel. At the outer most
layers, the polymer is diluted to the point where it no longer has structural integrity and
dissolves or wears away. This complex gelatinous layer controls the release of drugs by two
mechanisms.
1. Water-soluble drugs released by diffusion out of the gel layer.
2. Drugs released by erosion of the gel regardless of drug solubility in the dissolution
media. A water insoluble drug is exposed through erosion.

Fig 1.2: Drug release in swellable matrix system

INTRODUCTION
12


Fig1.3: Zones in swellable matrix system

When drug released from a matrix is controlled by diffusion through the polymeric matrix, its
release kinetics obeys Ficks 1
st
& 2
nd
laws
30
:
J = -D
(Eq. 1.1)
= - D
(Eq. 1.2)
Where J represents the diffusional flux of the drug; D is the diffusion coefficient of
the drug; C is the concentration of the drug; and x the distance of diffusion.
When drug release is dominated by surface erosion Korsmeyer and peppas developed
a general model for drug release from a planar matrix containing dissolved drug.
= Kt
n
(Eq. 1.3)
log
= logk + n log t (Eq. 1.4).

INTRODUCTION
13


1.5 DRUG PROFILE:
1.5.1 DIVALPROEX SODIUM
Divalproex sodium (DVP) is an anticonvulsant that contains valproic acid and sodium
valproate in a one to-one molar ratio. This medication has recently been shown to be effective
in treatment of acute mania
31
and depression
32
, suggesting that, like lithium, it has antimanic
and antidepressant properties
Fig 1.4: Chemical Structure of Valproic acid

.
Fig 1.5: Chemical Structure of Divalproex Sodium

INTRODUCTION
14


Table no 1.1: Physico Chemical Properties of Divalproex Sodium

1.5.2 Site and Mode of Action:
33, 34, 35

Divalproex Sodium is active against both pentylenetetrazol and maximal electroshock
seizures. Divalproex Sodium blocks sustained high-frequency repetitive firing of neurons in
culture at therapeutically relevant concentrations. Its action against partial seizures may be a
consequence of this effect on Na+ currents. Blockade of NMDA receptor-mediated excitation
may also be important. Much attention has been paid to the effects of Divalproex Sodium on
GABA. Several studies have shown increased levels of GABA in the brain after
administration of Divalproex Sodium, although the mechanism for this increase remains
unclear. An effect of Divalproex Sodium to facilitate glutamic acid decarboxylase (GAD), the
enzyme responsible for GABA synthesis, has been described. An inhibitory effect on the
GABA transporter GAT-1 may contribute. At very high concentrations, Divalproex Sodium
inhibits GABA-T in the brain, thus blocking degradation of GABA. However, at the
relatively low doses of Divalproex Sodium needed to abolish pentylenetetrazol seizures, brain
GABA levels may remain unchanged. Divalproex Sodium produces a reduction in the
aspartate content of rodent brain, but the relevance of this effect to its anticonvulsant action is
not known. At high concentrations, Divalproex Sodium has been shown to increase
membrane potassium conductance. Furthermore, low concentrations of Divalproex Sodium
Description White or almost white crystalline powder
Chemical name
compounded from sodium valporate and
valporic acid in 1:1 ratio
Molecular formula C
8
H
16
O
2
C
8
H
15
O
2
Na
Molecular weight 310.41
Solubility
Soluble in Ethanol (95%), Methanol, IPA, Partially
soluble in water and ether
Melting Point 222 C
Functional category
Mania, Epilepsy (Complex partial, simple and
complex petit mal), Migraine
Pharmacopoeial status USP
Storage conditions
Store in air tight containers, Protect from light, at a
temperature between 2
0
C and 8
o
C
INTRODUCTION
15


tend to hyperpolarize membrane potentials. These findings have led to speculation that
Divalproex Sodium may exert an action through a direct effect on the potassium channels of
the membrane.
Divalproex Sodium probably owes its broad spectrum of action to more than one molecular
mechanism.
1.5.3 Pharmacokinetics:
34,35

Absorption and distribution:
Valproate is well absorbed following an oral dose, with bioavailability greater than
80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and
decreased toxicity may result if the drug is given after meals.
Valproic acid is 90% bound to plasma proteins, although the fraction bound is
somewhat reduced at blood levels greater than 150 g/mL Since valproate is both highly
ionized and highly protein bound, its distribution is essentially confined to extracellular
water, with a volume of distribution of approximately 0.15 L/kg.

Metabolism and excretion:
Sodium valproate is extensively metabolised in the liver and has a t
1/2
of 13 hrs. It is
90% bound to plasma albumin. Sodium valproate is a nonspecific inhibitor of metabolism,
and indeed inhibits its own metabolism. Sodium valproate does not induce drug metabolising
enzymes but its metabolism is enhanced by induction due to other drugs, including
antiepileptics
Clearance for valproate is low; its half-life varies from 9 hours to 18 hours. At very high
blood levels, the clearance of valproate is dose-dependent. There appear to be offsetting
changes in the intrinsic clearance and protein binding at higher doses. Approximately 20% of
the drug is excreted as a direct conjugate of valproate.

Drug Interactions
As noted above, the clearance of valproate is dose-dependent, caused by changes in
both the intrinsic clearance and protein binding. Valproate inhibits its own metabolism at low
doses, thus decreasing intrinsic clearance. At higher doses, there is an increased free fraction
of valproate, resulting in lower total drug levels than expected. It may be clinically useful,
INTRODUCTION
16


therefore, to measure both total and free drug levels. Valproate also displaces phenytoin from
plasma proteins. In addition to binding interactions, valproate inhibits the metabolism of
several drugs, including phenobarbital, phenytoin, and carbamazepine, leading to higher
steady-state concentrations of these agents. The side effects and toxicity of phenytoin are
enhanced. The inhibition of phenobarbital metabolism may cause levels of the barbiturate to
rise precipitously, causing stupor or coma.

LITERATURE REVIEW
17


2. REVIEW OF LITERATURE

Emilio perucca, repoted a detailed introduction to anti-epileptic drugs giving the
mechanism of action of each class of anti-epileptic drugs, explaining the efficacy spectrum,
clinical pharmacokinetics and therapeutic drug monitoring for each class. The paper also
focused on adverse effect profile and drug interaction. Concluding that anti-epileptic drugs
differs from other in terms of pharmacological properties, efficacy spectrum, side effect
profile, interaction potential and cost.
36
Kumar et al proposed oral extended release drug delivery system as a promising
approach, stating the suitable candidate for extended release drug delivery system along with
merits and demerits of extended release drug delivery system. They briefly explained the
factors affecting the release from extended release drug delivery system, different polymers
used with their classification. They concluded that the extended release formulations are
known to increase the effectiveness of drugs with short half-life and also improve patient
compliance by reducing the dosing frequency.
37
Manivannan et al developed an extended release once a day formulation of divalproex
sodium using direct compression method. The direct compression technique using the rate
controlling polymers like HPMC K100M, HPMC K4M was found to could produce a stable
product.
38
Arunachalam et al developed an extended release once a day formulation of
divalproex sodium using direct compression the results obtained were found to be within the
specification limits and the optimized batch was found to be stable showing zero order
release kinetics.
39
Fagiolino et al reported the actual bioavailability of divalproex sodium extended
release tablet. The absolute oral bioavailability of divalproex sodium is 89% though the oral
absorption of the drug was practically 100%. They also stated different formulas to calculate
the ratio of drug absorption for divalproex sodium ER and DR tablets.
40

Jeganath et al worked on the stability of divalproex sodium ER tablets prepared by
direct compression. The physical and chemical properties of the tablets were assessed during
three months (accelerated stability). The Divalproex sodium tablet prepared by direct
compression were stable with good in vitro drug release.
41

DIVALPROEX SODIUMER
AIM AND OBJECTIVE
18


3. AIM AND OBJECTIVE

The primary objective of the study was to formulate an extended release tablet of
DIVALPROEX SODIUM that is likely to have fewer side effects. The tablet developed may
maintain effective plasma concentration of drug over a 24 hour dosing period and thus
improve patient compliance.
The specific objectives to be achieved include:
1) To formulate an extended release dosage form.
2) To formulate a dosage form that will permit once-a-day dosing.
3) To evaluate the prepared extended release tablets.
4) To perform the stability studies.

MATERIALS & METHODS
19


4. MATERIALS AND METHODS
4.1 Materials used for the study:
Table 4.1: List of materials used in the study
S.No Material Manufacturer
Intra granular ingredients
1 Divalproex Sodium Katwijk Chmie bv
2 Hypromellose USP (Benecel 874) Aqualon
3 Pregatinized Starch USNF (Starch 1500) Colorcon
4 Mannitol USP (Mannitol 35) Roquette
Binder Ingredients
5
Polyacrylate Dispersion 40 Percent (Eudragit NE 40
D)
Evonik Industries
6 Purified Water
Extra Granular Ingredients
7
Silicified Microcrystalline Celluose (Prosolv SMCC
50)
JRS Pharma
8 Silicon Dioxide USNF (Syloid 244 FP) Grace Davision
Film Coating
9 Opadry II Grey 41L57504 Colorcon

MATERIALS & METHODS
20


4.2 Equipments used in the study:
Table 4.2: List Equipments used in the study
S.No Equipment Manufacturer Model No.
1 Electronic Balance Sartorius, Germany BT 2233
2 Tap density tester Electrolab, Mumbai ET 1020
3
Electromagnetic Sieve
shaker
Restech, New Delhi AS 200
4 Double cone blender Rimek, Ahmedabad KALWEKA HD 410 AC
5 Laboratory Stirrer Remi, Mumbai RQT 124 A
6 Rotor Mixer Granulator Gansons, Mumbai HSMG
7 Rapid air Dryer Restech, New Delhi TG 100
8 Loss on Drying Machine Sartorius, Germany MA 100
9 Multimill Grovers International Lab scale multi mill 116
10 Comill Quadro, Canada U5-0280
11
Compression Machine 20
station
Cadmach, Ahmedabad CMD 4
12 Hardness tester Varian, Carolina, US VK 200
13 Friabilator Electrolab, Mumbai EF 2
14 Vernier Caliper Multiyoyo Japan
15 Coating Machine Gansons, Mumbai GAC 250/375
16 Peristaltic Pump Electrolab, Mumbai PP 210 V
17
Dissolution tester Type II
USP
Electrolab, Mumbai TDT 08L
18 pH tester
Eutech Instruments,
Singapore
pH 1500
19 Magnetic stirrer
Deepali Magnetic
Stirrer, Mumbai
MS 1

MATERIALS & METHODS
21


4.3 CALIBRATION CURVE OF DIVALPROEX SODIUM BY UV SPECTRO
PHOTOMETRIC METHOD:
Standard curve for Divalproex Sodium with 0.05M Phosphate buffer with 75mM SDS,
pH 5.5:
To prepare standard solution of solvent/buffer 21.6g of sodium dodecyl sulphate/SDS,
6.9g of sodium dihydrogen phosphate monohydrate, and 0.12g of sodium hydroxide were
dissolved in 1l of water and pH was adjusted to 5.5. 50mg of Divalproex Sodium was
weighed and transferred into 50ml volumetric flask and volume was made up using the
buffer. About 1ml of the above solution was transferred to 10ml volumetric flask and volume
was made up with standard buffer solution. Aliquots of 0.2 ml, 0.4 ml, 0.6 ml, 0.8 ml, 1 ml
were pipetted out from stock solution and diluted to 10 ml with standard buffer solution to
give standard solutions having concentrations of 2mcg/ml, 4mcg/ml, 6mcg/ml, 8mcg/ml and
10mcg/ml. The absorbance of the solutions was determined at 210nm against standard buffer
solution as the blank. The standard curve of divalproex sodium was obtained by plotting
absorbance on Y-axis against concentration on X-axis.
4.4 INNOVATOR PRODUCT DETAILS:
The objective of the present work was to match the release characteristics of the
developed tablets with that of innovator product (DEPAKOTE

ER 500-Abott Pharmaceuticals
PR LTD). The innovator product was evaluated for physical properties, drug content and in-
vitro drug release to set a target for the product to be developed.
Fig 4.1: Innovator (DEPALOTE ER Abott Pharmaceuticals PR LTD) Brand Label

MATERIALS & METHODS
22


4.5 PREFORMULATION STUDIES:
Preformulation can be defined as investigation of physical and chemical properties of
drug substance alone and when combined with excipients. Preformulation studies are the first
step in the rational development of dosage form of a drug substance. The objectives of
Preformulation studies are to develop a portfolio of information about the drug substance,
which helps in formulation development. The drug was evaluated for the following
parameters during Preformulation studies:
4.5.1 Bulk Density (BD):
Twenty five grams of drug which was previously passed through #20 sieve was
accurately weighed and transferred in 100 ml graduated cylinder. The powder was carefully
levelled without compacting, and the unsettled apparent volume was read. The apparent bulk
density in g/ml was calculated by the following formula;
Bulk density = Weight of powder / Bulk volume .. eq.1
4.5.2 Tapped bulk density (TD):
Twenty five grams of drug which was previously passed through #20 sieve was
weighed accurately then transferred in 100 ml graduated cylinder. The cylinder containing
the sample was mechanically tapped by raising the cylinder and allowed to drop under its
own weight using mechanically tapped density tester that provides a fixed drop of 142 mm
at a nominal rate of 250 drops per minute. The cylinder was tapped for 250 times initially and
the tapped volume (V
1
) was measured to the nearest graduated units, the tapping was
repeated for an additional 750 times and the tapped volume (V
2
) was measured to the nearest
graduated units. If the difference between the two volumes is less than 2% then final the
volume (V
2
), the tapped bulk density in g/ml was calculated by the following formula:
Tapped Density = Weight of powder / Tapped volumeeq.2

MATERIALS & METHODS
23


4.5.3 Carrs index:
The compressibility of powder was determined by Carrs compressibility index.
Carrs Index (%) = [(TD-BD) x100]/TD eq. 3
Table No: 4.3 Limits for Carrs Index
Excellent <10
Good 11 15
Fair 16 20
Passable 21 25
Poor 26 31
Very poor 32 37
Very very poor >38

4.5.4 Hausners ratio:
Hausners ratio was determined by using the following equation.
Hausners Ratio = TD / BD .eq.4
Table No: 4.4 Limits for Hausners Ratio
Excellent 1.00 1.11
Good 1.12 1.18
Fair 1.19 1.25
Passable 1.26 -1.34
Very poor 1.35 -1.45
Very very poor >1.60
MATERIALS & METHODS
24


4.5.5 Angle of repose:
The angle of repose of drug was determined by the funnel method. The accurately
weighed powder blend was taken in the funnel. The height of the funnel was adjusted in such
a way that the tip of the funnel just touched the apex of the powder blend. The powder blend
was allowed to flow through the funnel freely on to the surface. The diameter of the powder
cone was measured and angle of repose was calculated using the following equation.
Tan = h/r ..eq.5
Where, h and r were the height and radius of the powder cone respectively.

Table No: 4.5 Effect of angle of repose on flow property
Angle of Repose () Type of Flow
< 20 Excellent
20-30 Good
30-34 Passable
>35 Very poor

4.6 COMPATIBILITY STUDIES:

The objective of the study was to assess the compatibility of Divalproex Sodium with
excipients used in the formulation. Drug: Excipient blends in the ratios specified in the table
were incubated in clear, molded glass vials closed with LDPE caps at 60
0
C for 15 days and at
40
0
C / 75% RH for a period of one month and observed for change in physical and chemical
attributes.
MATERIALS & METHODS
25


Table No 4.6: Drug: Excipient ratio for compatibility studies
S.no Composition details Drug: excipients
1 Divalproex sodium NA
2 Divalproex sodium + pregelatinized starch(starch 1500) 1:5
3 Divalproex sodium + HPMC (Benecel Mp 874 Pharm) 1:5
4 Divalproex sodium + mannitol 35 1:5
5
Divalproex sodium + polyacrylate dispersion 40 percent
( eudragit NE 40 D)
1:5
6
Divalproex sodium + silicified microcrystalline
cellulose ( Prosolv SMCC 50)
1:5
7
Divalproex sodium + silicon dioxide USNF ( Syloid 244
FPP )
1:2
8 Divalproex sodium + Opadry II Gray 41L57504 1:1
9 Divalproex sodium + Opadry white 06L58769 1:1

4.7 X-RAY POWDER DIFFRACTION:
The initial and three months samples of Divalproex Sodium ER tablets of 40
0
C/75%
RH conditions were analysed by X-ray powder diffraction to evaluate any change in the
polymorphic form of Divalproex Sodium during formulation preparation and subsequent
storage at accelerated stability conditions. The excipients used in the preparation are almost
amorphous in nature and show only few diffraction peaks of weak intensity, which do not
interfere in the polymorphic identity conformation of Divalproex Sodium in the formulation.

MATERIALS & METHODS
26


4.8 MANUFACTURING PROCESS DEVOLOPMENT:
The manufacturing process of Divalproex Sodium Extended Release Tablets is as follows:
4.8.1 SIFTING:
a) Divalproex sodium was passed through multi mill with 1.5 mm screen at low speed
then mannitol 35 was passed for rinsing.
b) The above material (drug + mannitol 35) is sifted through 30# sieve.
c) Hypromellose was sifted through 30 # sieve.
d) Pregelatinised starch was sifted through 30 # sieve.
4.8.2 GRANULATING DISPERSION:
a) Polyacrylate dispersion 40% was passed through 100 # nylon cloth.
4.8.3 DRY MIXING:
a) The sifted material of b,c,d of first step was loaded in RMG.
b) Dry mixed for 10min at slow impellar speed and chopper off.
4.8.4 GRANULATION:
a) Filtered polyacrylate dispersion 40% of step 2 was added to the above dry mix for
over 4 min with slow impellar speed and slow chopper speed.
b) If required extra quantity of purified water (NMT 6%) was added over a period of
30sec with slow impellar speed and slow chopper speed.
c) The wet mass was kneaded for 30sec or more with slow impellar speed and high
chopper speed, till desired mass is obtained.
d) The wet mass was unloaded at slow impellar speed and high chopper speed.
4.8.5 DRYING AND MILLING:
a) The wet mass was airdried in air dryer for 10min followed by drying at an inlet
temperature of 455
0
C to get LOD in range of 5-8% w/w at 80
0
C in auto-mode
using suitable moisture analyser.
MATERIALS & METHODS
27


b) The semi dried granules were milled using multi mill through 6 mm screen at
medium speed.
c) The milled granules were dried at an inlet temperature of 455
0
C in air dryer to get
LOD in range of 3-5% w/w at 80
0
C in auto-mode using suitable moisture analyser.
d) The dried granules were again multi milled using 1.5 mm screen at medium speed.
e) The milled granules were dried at 605
0
C in air dryer to get LOD not more than
2% w/w at 80
0
C in auto-mode using suitable moisture analyser.
f) The above granules were sifted through 20 # and the passed granules were collected
in double polybag.
g) The retains were collected and multi milled using 1.5 mm screen at medium to fast
speed.
h) The milled granules were added to the granules from step.F

4.8.6 SIFTING:
a) SMCC was sifted through 40#.
b) Silicon dioxide was sifted through 40#.
4.8.7 BLENDING:
a) The collected granules were loaded into low shear blender.
b) SMCC was added to the above step and blended for 15min.
c) Silicon dioxide was added to the above step and blended for 30min.
d) The lubricated granules were stored in double polyethene lined triple laminated
aluminium bags with desiccant if unloaded from the blender.
4.8.8 BLEND SAMPLE ANALYSIS:
a) Blend sample was sent for analysis.
4.8.9 COMPRESSION:
a) The blend was loaded into the hopper and continued with compression using
suitable compressing machine maintaining the following parameters:

MATERIALS & METHODS
28


Table no 4.7: Parameters for Tablet Compression
Shape
White to off white, oval shaped uncoated
tablets with plain surface on both sides.
Tooling 18.8 X 9.7mm oval shaped punches and dies.
Average weight
1010mg 2%
(989.8mg-1030.2mg)
Hardness 10-18Kp
Thickness
7.90.4mm
(7.5mm-8.3mm)
friability NMT 0.8% w/w
Weight variation 5% of target weight

4.8.10 FILM COATING DISPERSION / SUSPENSION PREPARATION:
a) Purified water was taken in plastic beaker and stirred with suitable stirrer.
b) Opadry II grey was dispersed into above water while stirring and continued
stirring for 45min.
4.8.11 FILM COATING:
a) The compressed tablets were loaded into perforated coating pan and pre warmed
at inlet temperature of 6010
0
C with an intermittent inching of coating pan.
b) Spraying of opadry II grey suspension was started at an inlet temperature of
6010
0
C when product temperature of 45
0
C was attained.
c) The coating parameters were recorded.
d) Coating was continued to get 2.75-3.25% w/w build up.
e) Spraying was stopped when the required build up percentage was attained and
then the coated tablets were dried for 15min at 6010
0
C.
f) The tablets were unloaded and continued for packing.

MATERIALS & METHODS
29


Fig 4.2: Schemtic representation of Manufacturing Process

Sifting and
Dry Mixing
Wet
Granulation
Drying and
Milling
Blending
Compression
Film Coating
& Packing

BLENDER

ROTOR MIXER GRANULATOR

MULTI MILL

COMPRESSION
MACHINE
MATERIALS & METHODS
30


Table no. 4.8: Formulations F1-F8
S.No Material
Formulation Code F (mg)
F1 F2 F3 F4 F5 F6 F7 F8
Intra granular ingredients
1 Divalproex Sodium 538.1 538.1 538.1 539.34 538.1 538.1 538.1 538.1
2
Hypromellose USP
(Benecel 874)
161.6 171.7 171.7 171.7 171.7 171.7 171.7 171.7
3
Pregatinized Starch USNF
(Starch 1500)
48.2 38.1 59.60 55.86 59.60 56.20 58 57.1
4
Mannitol USP (Mannitol
35)
120 120 98.2 101 101 101 101 101
Binder Ingredients
5
Polyacrylate Dispersion
40 Percent (Eudragit NE
40 D)
47.1 47.1 47.1 47.1 47.1 47.1 47.1 47.1
6 Purified Water qs qs qs qs qs qs qs qs
Extra Granular Ingredients
7
Silicified Microcrystalline
Celluose (Prosolv SMCC
50)
50 50 50 50 47.5 50 50 50
8
Silicon Dioxide USNF
(Syloid 244 FP)
45 45 45 45 45 45.9 44.1 45
Film Coating
9 Opadry II Grey 41L57504 qs qs qs qs qs qs qs qs

MATERIALS & METHODS
31


4.9 Evaluation of Extended Release Tablets:
Weight variation test
Individual weights of 20 capsules were taken randomly and the average weight was
calculated by using the following formula.

4.10 IN VITRO DISSOLUTION STUDY

Table No: 4.9 Dissolution at acid stage
Parameters
Dissolution at acid stage
media

Media 0.1N HCl

Apparatus USP II apparatus (Paddle)

RPM 50

Amount of media 500ml

Time 45min

Temperature 37 5
0
C

There is no release of any drug substance during this stage
Table No: 4.10 Dissolution at buffer stage
Parameters
Dissolution at Buffer stage
media

Media
0.05M Phosphate buffer with 75mM
SDS, pH 5.5

Apparatus USP II apparatus (Paddle)

RPM 100

Amount of media 900ml

Time 24hrs

Temperature 37 5
0
C

MATERIALS & METHODS
32


The absorbance of sample is measured in 1cm cell on suitable UV Spectrophotometer at
210nm, using medium as blank and the absorbance was recorded.
4.11 STABILITY STUDIES:
Stability studies were an integral part of the drug development program and are one of
the most important areas in the registration of pharmaceutical products. The purpose of
stability testing is to provide evidence on how the quality of a drug substance or drug product
varies with time under the influence of a variety of environmental factors such as temperature,
humidity, light and enables recommended storage conditions, re-test periods and self-
half-lives to be established. Degradation products, degradation pathway were determined
by stability assessment pathway. In these types of studies the tablets were stored in
suitable containers or blister packages and stability study is conducted as per ICH guidelines.
The product was analysed at intervals for various parameters which may include assay of
active ingredient, measurement of known disintegration time, dissolution time, appearance,
etc., Stability studies has been conducted at following conditions.
Storage conditions
Accelerated: - 40 C 2 C /75%RH 5%RH
As per ICH guidelines, the samples for stability analysis must be exposed to an
environment of 40C 2C / 75%RH 5% RH for a period of 6 months. As per the standard
protocol the samples must be analysed at 0, 1, 2, 3 and 6 months time points.
Accelerated stability studies were performed for the final optimized formulation (F8).
Samples were analysed at 1, 2, 3 months time points.

RESULTS
33


5. EXPERIMENTAL RESULTS

5.1 CALIBRATION CURVE OF DIVALPROEX SODIUM BY UV
SPECTROPHOMETRIC METHOD:
Standard graph of Divalproex Sodium in 0.05M Phosphate buffer with 75mM SDS, pH
5.5 at max 210.0 nm

Standard curve of Divalproex Sodium was found to be linear over a concentration range of 2-
10g/ml with R
2
=0.997.
The absorbance values of different concentrations are shown in table 5.1 and standard curve
is shown in the figure 5.1.
Table No 5.1: Data for calibration curve of Divalproex Sodium
Concentration(mg/ml) Absorbance at 210nm

0 0.01

2 0.06

4 0.132

6 0.212

8 0.268

10 0.327

RESULTS
34


Figure 5.1: Standard graph of Divalproex Sodium

5.2 INNOVATOR PRODUCT DETAILS:

Table No 5.2: Physico chemical properties of innovator product DEPAKOTE ER
500mg
Parameters Observation

Description
Grey ovaloid, film coated tablets imprinted with a and HC on one
side and other side plain
Market USA
Label Claim
Each tablet contains Divalproex Sodium equivalent to Valproic acid
500mg
Average
weight(mg)
1039
Coated/ Uncoated Film coated
Length(mm) 19.02
Thickness(mm) 8.11
Water by KF (%) 2.67

0.01
0.07
0.132
0.212
0.268
0.327
y = 0.0323x + 0.0085
R = 0.9978
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 2 4 6 8 10 12
A
b
s
o
r
b
a
n
c
e

Concentration g/ml
Standard curve of Divalproex Sodium in 0.05M Phosphate buffer
with 75mM SDS, pH 5.5

Series1
RESULTS
35


Innovator In-vitro Drug Release Profile: In 0.05M Phosphate buffer with 75mM SDS

The in-vitro drug release profile of innovator product is shown in table no. 5.3 &
figure no. 5.2
Table No: 5.3 In-vitro drug release profile of innovator product
TIME(Hr) % DRUG RELEASE
3 21
6 33
9 47
12 60
15 71
18 85
21 92
24 98

Figure 5.2: Innovator Drug Release profile

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator Drug Release Profile
RESULTS
36


5.3 PREFORMULATION STUDIES:
API CHARECTERIZATION:
APPEARANCE: White or almost white crystalline powder.
SOLUBILITY: The drug is highly soluble in Chloroform, freely soluble in Methanol, and in
Ethyl Ether, Soluble in Acetone, Partially soluble in Acetonitrile

The results of pre formulation studies of API were shown in table 5.4
Table No: 5.4 API Characterization

S. No Characteristics Results
1 Bulk Density (gm/ml) 0.325
2 Tapped Density (gm/ml) 0.420
3
Compressibility index
(%)
22.472
4 Hausers ratio 1.292
6
Loss on drying (LOD)
(%)
2.0
7
max
210 nm
RESULTS
37


5.4 Drug excipient interaction studies:
The results of Drug:Excipient compatibility studies were shown in table no 5.5
Physical compatibility:
Table No 5.5: Drug: Excipients Physical compatibility study
S.no
Composition
details
Drug:
excipients
Description
initial
60
0
C 40
0
C/75%RH
15days 1 month
1
Divalproex
sodium
NA
White
color
powder
NCC NCC
2
Divalproex
sodium +
pregelatinized
starch(starch
1500)
1:5
White
color
mixture
White to
off white
color
mixture
White to off white
color mixture
3
Divalproex
sodium + HPMC
(Benecel Mp 874
Pharm)
1:5
White to
off white
color
mixture
NCC NCC
4
Divalproex
sodium +
mannitol 35
1:5
White
color
mixture
NCC NCC
5
Divalproex
sodium +
polyacrylate
dispersion 40
percent ( eudragit
NE 40 D)
1:5
White
color
dispersion
Off white
color hard
cake
Off white color
hard cake
6
Divalproex
sodium +
silicified
microcrystalline
cellulose (
Prosolv SMCC
50)
1:5
White to
off white
color
mixture
Off white
to pale
yellow
color
mixture
NCC
7
Divalproex
sodium + silicon
dioxide USNF (
Syloid 244 FPP )
1:2
White
color
mixture
NCC NCC
8
Divalproex
sodium + Opadry
II Gray
41L57504
1:1
Gray color
mixture
NCC
NCC

NA = not applicable
NCC = no characteristic change
RESULTS
38


Chemical compatibility: The results of Drug:Excipient compatibility studies were shown in
table no 5.6
Table No 5.6: Drug: Excipients Chemical compatibility study
S.No
Composition
details
Drug :
Excipients
Assay ( % )
Initial
600C 400C/75%RH
15days 1 month
1
Divalproex
sodium
NA 101.0 100.2 91.2
2
Divalproex
sodium +
pregelatinized
starch(starch
1500)
1:5 101.1 98.8 82.9
3
Divalproex
sodium + HPMC
(Benecel Mp 874
Pharm)
1:5 103.3 100.3 105.5
4
Divalproex
sodium +
mannitol 35
1:5 102.3 100.7 104.4
5
Divalproex
sodium +
polyacrylate
dispersion 40
percent ( eudragit
NE 40 D)
1:5 96.6 * *
6
Divalproex
sodium +
silicified
microcrystalline
cellulose (
Prosolv SMCC
50)
1:5 101.4 99.4 104.0
7
Divalproex
sodium + silicon
dioxide USNF (
Syloid 244 FPP )
1:2 94.0 95.1 103.2
8
Divalproex
sodium + Opadry
II Gray
41L57504
1:1 101.0 96.1 100.2
NA = Not applicable
* = Forms a hard cake which cannot be redispersed and hence accurate analytical results not available
RESULTS
39


5.5 X-RAY Powder diffraction study:
The X-ray powder diffraction pattern of Divalproex sodium extended release tablets exhibits
the diffraction peaks characteristic of Divalproex sodium, thereby indicating no change in the
polymorphic form of divalproex sodium during formulation, preparation as well as during
stability storage period.
An overlay of the X-ray powder diffraction pattern of the following samples is enclosed
herewith:
a) Divalproex sodium API
b) Divalproex sodium Extended release tablets ( initial )
c) Divalproex sodium Extended release tablets ( after storage at 40
0
C / 75% RH for a
period of 3months)
d) Placebo
Fig 5.3: X-Ray Powder Diffraction Study of Divalproex Sodium with Excipients

RESULTS
40


5.6 FORMULATION DIVALPROEX SODIUM EXTEDED RELEASE
TABLETS
The extended release matrix formulation of divalproex sodium was achieved by wet
granulation method.
EVALUATION OF DIVALPROEX SODIUM EXTENDED RELEASE TABLETS
Table No 5.7: Evaluation of F1:
Parameters Values
DRY MIX
Bulk density (g/ml) 0.309
LUBRICATED BLEND
Tapped density (g/ml) 0.589
Compressibility index ( % ) 20.515
Hausners ratio 1.17
CORE TABLET
Hardness ( KP ) 12.1
Thickness ( mm ) 8.23
Friability ( % m/m ) Nil
Average weight ( mg ) 1011.2
Weight variation ( mg ) 1008-1013
FILM COATED TABLET
Weight ( mg ) 1035

Table No: 5.8: In-vitro dissolution Data of F1:
Acid stage
S.No: Time (hrs) % Drug release
1 45Min 0
Buffer stage
1 3 20
2 6 32
3 9 45
4 12 54
5 15 63
6 18 75
7 21 82
8 24 88

RESULTS
41


Figure 5.4: Comparative I nvitro drug release profile of F1 with I nnovator

Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.18
CORE TABLET
FILM COATED TABLET
Weight ( mg ) 1042

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F1
RESULTS
42


Table No 5.10: In-vitro dissolution Data of F2:
Acid stage
1 45Min 0
Buffer stage
1 3 21
2 6 32
3 9 43
4 12 51
5 15 65
6 18 73
7 21 86
8 24 90

Figure 5.5: Comparative Invitro drug release profile of F2 with Innovator

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F2
RESULTS
43


Table No5.11: Evaluation of F3:
Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.27
CORE TABLET
FILM COATED TABLET
Weight ( mg ) 1037.5

Acid stage
1 45Min 0
Buffer stage
1 3 20
2 6 36
3 9 45
4 12 54
5 15 69
6 18 77
7 21 85
8 24 92

RESULTS
44



Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.25
CORE TABLET
FILM COATED TABLET
Weight ( mg ) 1042

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F3
RESULTS
45


Acid stage
1 45Min 0
Buffer stage
1 3 22
2 6 40
3 9 53
4 12 60
5 15 69
6 18 80
7 21 85
8 24 92


0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F4
RESULTS
46


Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.21
CORE TABLET
FILM COATED TABLET

Acid stage
1 45Min 0
Buffer stage
1 3 22
2 6 40
3 9 53
4 12 60
5 15 69
6 18 80
7 21 85
8 24 92

RESULTS
47



Table No 5.17 Evaluation of F6:
Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.19
CORE TABLET
FILM COATED TABLET

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F5
RESULTS
48


Acid stage
1 45Min 0
Buffer stage
1 3 23
2 6 42
3 9 50
4 12 59
5 15 68
6 18 75
7 21 85
8 24 94


0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F6
RESULTS
49


Table No 5.19 Evaluation of F7:
Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.23
CORE TABLET
FILM COATED TABLET
Weight ( mg ) 1039

Acid stage
1 45Min 0
Buffer stage
1 3 24
2 6 42
3 9 51
4 12 59
5 15 69
6 18 77
7 21 88
8 24 95

RESULTS
50



Parameters Values
DRY MIX
LUBRICATED BLEND
Hausners ratio 1.26
CORE TABLET
FILM COATED TABLET
Weight ( mg ) 1049

0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F7
RESULTS
51


Table No 5.22 In-vitro dissolution Data of F8:
Acid stage
1 45Min 0
Buffer stage
1 3 25
2 6 44
3 9 53
4 12 63
5 15 79
6 18 85
7 21 92
8 24 99


0
20
40
60
80
100
120
0 5 10 15 20 25 30
Innovator
F8
RESULTS
52


5.7 ACCELERATED STABILITY DATA OF FORMULATION (F
8
):
Table No 5.23 Accelerated Stability Data of F8:
Product Name Divalproex Sodium ER 500mg Tablets (F
8
)
Packing HDPE Heavy weight container with 1g Silica gel (100s count)
Condition 40
0
C/75%RH
Period Initial 1M 2M 3M
Assay (%) 100.7 99.2 98.6 98.9
Appearance
White to off
white color
mixture
NCC NCC NCC
Dissolution % Drug Released
3 21 22 21 23
6 37 38 35 39
9 50 51 49 50
12 61 62 57 59
15 72 71 66 69
18 82 78 75 76
21 89 85 84 85
24 97 92 90 93

DISCUSSION
53


6. DISCUSSION

The present work aims to formulate extended release matrix tablets of Divalproex
sodium with a view to reduce the incidence of side effects associated with conventional
tablets and reduce the frequency of drug administration thereby to improve patient
compliance.

The calibration curve of Divalproex sodium was constructed by UV-
spectrophotometer. It was found that the curve was linear over a concentration range of 2-10
g/ml with r
2
value of 0.997.
Hausners ratio = 1.292%).
The drug excipient compatibility studies indicated that there was no physical change
in the drug when mixed with various excipients and subjected to accelerated stress conditions
(40
0
X-Ray diffraction studies of the drug and excipients indicated that the characteristic
peaks of the drug were retained in the mixture there by indicating absence of interaction
between the drug and the excipients.
The intention of present work was to develop a product having release profile similar
to the innovator product. Hence the innovator product (DEPAKOTE
ER) was evaluated to

determine the characteristics of final product. Based on the percentage drug release of the
innovator product, the target release was calculated.
In formulation F1 polymer concentration was 16%, drug concentration was 53.27%.
Initially the drug release was same as that of innovator but to the end it failed to maintain the
drug release as that of innovator. This may be due to the low polymer concentration drug
release rate was not maintained.
DISCUSSION
54


In formulation F2 polymer concentration was increased to 17% by decreasing the
diluent concentration (strach1500) to 3.77%. The formulation failed to achieve the innovator
drug release this may be due to increased polymer concentration.
In formulation F3 polymer concentration was kept same as that of F2 and diluent
concentrations were altered, concentration of strach1500 was increased to 5.90% and
concentration of mannitol35 was decreased to 9.7%. In this formulation drug release was not
constant, however it does not reached innovator concentration. This may be due to the
increased concentration of starch 1500.
In formulation F4 drug concentration was increased to 53.4% by lowering the
concentration of starch1500 to 5.53%. And mannitol was increased to 10%. Initially the drug
release was high but slowly it came down. The drug release was not linear. Increased drug
concentration did not help.
In formulation F5 the concentration of prosolv SMCC 50 was lowered to 4.7% and
the concentration of starch1500 was increased 5.90%. The drug release was not linear same
as that of F4.
In formulation F6 the concentration of syloid 244 FP (silicon dioxide) was increased
to 4.54%, decreasing the starch 1500 concentration to 5.56%. Initially rapid drug release was
observed and then the drug concentration came down.
In formulation F7 syloid 244 FP concentration was reduced to 4.37% and starch 1500
concentration was increased to 5.74% the drug release same as that of F6.
In formulation F8 the concentration of starch1500 was decreased to 5.65% and the
drug concentration was kept to 53.27% all other concentration were kept same as that of F4.
Initially high drug concentration was observed but maintained all over the time period. The
percentage drug release for this formulation was maintained with innovator in close range.
Hence, formulation F8 was considered to be the optimized formulation based on
the values obtained from F4-F7 the increased concentrations of starch in the formulation
is affecting the drug release. The release profile of F8 was found to be very close to that
of innovator (%DR= 98).
The optimized final formulation was packed in HDPE heavy weight container with 1g
silica gel (100s count) and subjected for accelerated stability studies at 40C/75% RH for 3
DISCUSSION
55


months. The drug content and in vitro drug release was found to be 97, 92, 90, 93 for initial,
1
st
month, 2
nd
month, and 3
rd
month respectively. The results of stability studies indicated that
the developed product was stable.

CONCLUSION
56


7. CONCLUSION
The extended release tablets of divalproex sodium were prepared and different
formulations were subjected to various evaluation tests such as thickness, diameter, and
uniformity of weight and drug content, hardness friability, and in-vitro dissolution. The
results obtained were found to be within specification limits.
Of all the formulations formulation F
8
complies as per in-house specification with the
innovator sample. And hence, optimized batch (F
8
) is concluded as optimized formula due to
its good in-vitro release characteristics.
The formulated tablets were able to meet the set objectives. As the drug release was
found to be constant over a 24 hour period and found to be stable.

SUMMARY
57


8. SUMMARY
The present work aims to formulate extended release matrix tablets of Divalproex
sodium with a view to reduce the incidence of side effects associated with conventional
tablets and reduce the frequency of drug administration thereby to improve patient
compliance.

The calibration curve of Divalproex sodium was constructed by UV-
spectrophotometer. It was found that the curve was linear over a concentration range of 2-10
g/ml with r
2
value of 0.997.
Hausners ratio = 1.292%).
The drug excipient compatibility studies indicated that there was no physical change
in the drug when mixed with various excipients and subjected to accelerated stress conditions
(40
0
X-Ray diffraction studies of the drug and excipients indicated that the characteristic
peaks of the drug were retained in the mixture there by indicating absence of interaction
between the drug and the excipients.
The intention of present work was to develop a product having release profile similar to the
innovator product. Hence the innovator product (DEPAKOTE
ER) was evaluated to

determine the characteristics of final product. Based on the percentage drug release of the
innovator product, the target release was calculated.
In formulation F8 the concentration of starch 1500 was increased to 5.65% and the
drug concentration was kept to 53.27% all other concentration were kept same as that of F4.
Initially high drug concentration was observed but maintained all over the time period. The
percentage drug release for this formulation was maintained with innovator in close range.
Hence, formulation F8 was considered to be the optimized formulation in which
the release profile was found to be very close to that of innovator (%DR= 98).
SUMMARY
58


The optimized final formulation was packed in HDPE heavy weight container with 1g silica
gel (100s count) and subjected for accelerated stability studies at 40C/75% RH for 3
months. The drug content and in vitro drug release was found to be 97, 92, 90, 93 for initial,
1
st
month, 2
nd
month, and 3
rd
month respectively. The results of stability studies indicated that
the developed product was stable.
Once-a-day Divalproex sodium extended release tablets would be thus helpful in reducing
dosing frequency and decreasing the associated side effects, likewise increasing patient
compliance.

REFERENCES
59


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FORMULATION DEVOLOPMENT AND EVALUATION OF

DIVALPROEX SODIUM EXTENDED RELEASE TABLET

= logk + n log t (Eq. 1.4).

ER) was evaluated to

ER) was evaluated to

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