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COMPARISON OF IN-VITRO RELEASE PROFILE OF DICLOFENAC FROM
VARIOUS FORMULATIONS
By
Ms. Patel Ruchita Girishchandra, B.Pharm
Reg. No-04PU754
A dissertation submitted to the RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
In partial fulfillment of the requirements for the degree of
Master of Pharmacy In
PHARMACEUTICS
Under the Guidance of
Mr. Sreedharan, M.Pharm
Department of Pharmaceutics Nitte Gulabi Shetty Memorial Institute of Pharmaceutical Sciences
Mangalore – 575 005
December 2005
NITTE GULABI SHETTY MEMORIAL INSTITUTE OF
PHARMACEUTICAL SCIENCES MANGALORE – 575 005
Certificate
This is to certify that the dissertation entitled “COMPARISON OF
IN-VITRO RELEASE PROFILE OF DICLOFENAC FROM VARIOUS
FORMULATIONS” is a bonafide research work done by Ms. Patel
Ruchita Girishchandra submitted in partial fulfillment for the award of
the degree of “Master of Pharmacy” in Pharmaceutics of the “Rajiv
Gandhi University of Health Sciences”, Karnataka. This work was carried
out by her in the library and laboratories of NGSM Institute of
pharmaceutical sciences, Mangalore, under my guidance and direct
supervision.
Date : Mr. SREEDHARAN., M. Pharm., Place : Mangalore Assistant Professor, Dept. of Pharmaceutics
NGSM Institute of Pharmaceutical Sciences Mangalore - 575 005
NITTE GULABI SHETTY MEMORIAL INSTITUTE OF
PHARMACEUTICAL SCIENCES MANGALORE – 575 005
Endorsement
This is to certify that the dissertation entitled “COMPARISON OF
IN-VITRO RELEASE PROFILE OF DICLOFENAC FROM VARIOUS
FORMULATIONS” is a bonafide research work done by Ms. Patel
Ruchita Girishchandra under the direct supervision and guidance of
Mr. Sreedharan, M. Pharm, Assistant Professor, Department of
Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Mangalore.
Date : Prof. Dr.D. Satyanarayana , Place : Mangalore M. Pharm, Ph.D., FIC.
Director (PG and Research studies) NGSM Institute of Pharmaceutical Sciences
Mangalore - 575 005
NITTE GULABI SHETTY MEMORIAL INSTITUTE OF PHARMACEUTICAL SCIENCES
MANGALORE – 575 005
This is to certify that the dissertation entitled “COMPARISON OF
IN-VITRO RELEASE PROFILE OF DICLOFENAC FROM
VARIOUS FORMULATIONS” is a bonafide research work done by
Ms. Patel Ruchita Girishchandra under the direct supervision and
guidance of Mr. Sreedharan, M.Pharm, Assistant Professor, Department
of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences,
Mangalore.
Prof. M. V. Ramana, M. Pharm. Head, Department of Pharmaceutics NGSM Institute of Pharmaceutical Sciences, Mangalore - 575 005.
Prof. Dr. E.V.S.Subrahmanyam, M.Pharm, Ph.D., Principal NGSM Institute of Pharmaceutical
Sciences, Mangalore - 575 005.
Date :
Place : Mangalore
Date :
Place : Mangalore
Endorsement
ACKNOWLEDGEMENT
“Gratitude makes sense of our past, brings peace for today and creates a
vision for tomorrow”.
I humbly owe the completion of this dissertation work to the almighty for
his everlasting love and blessings on me.
It is a delightful moment for me, to put into words all my gratitude to my
esteemed guide Mr. Sreedharan, Assistant Professor, Dept. of pharmaceutics,
NGSMIPS, Mangalore, for his unstinted guidance.
At first, I consider it as a great privilege to express my heartfelt gratitude
and sincere thanks to Mr. Prabhakara Prabhu, Assistant Professor Dept. of
Pharmaceutics, NGSMIPS, Mangalore, for his valuable suggestions, constant
encouragement, optimism towards problems, till the moment I finished my work,
are highly admirable.
I am deeply indebted to Prof. Dr. D. Satyanaryana, Director (PG Studies
and Research), for his constant encouragement and ever willingness to provide
the necessary facilities during the entire course of study.
I specially convey my gratitude and warm thanks to Prof. Dr. E. V.S.
Subrahmanyam, Principal, for his support, valuable and generous help and
constant encouragement.
My deepest appreciation and heartfelt thanks to Prof. M. V. Ramana,
Head of the Department of Pharmaceutics for his valuable suggestions and help
in making my study a success. I cherish his co-operation throughout my life.
I specially thanks to Prof. Dr. R. Narayana Charyulu, M. Pharm, Ph D,
Departmaent of Pharmaceutics, Prof. C.G.Geetha Rao, Department of
Pharmaceutics, Mrs. Marina Koland, M. Pharm, Department of Pharmaceutics,
Mr. Ramkrishna Shabaraya, M. Pharm, Department of Pharmaceutics, for their
constructive suggestions.
My genuine thanks to Dr. Ishwar Bhat, Dr. Himja Ramana, Mrs. Jennifer
fernandes, Mr. Ronald fernandes, Mr. Revanasidappa, Mrs. Jane Jocob
Department of Pharmaceutical Chemistry, Dr. Arun B. Joshi,
Mr. Chandrashekar Department of Pharmacognosy and Phytochemistry.
Dr. Prashanth Shetty, Mr. Vijayanaryana, Mr. Yogendra Nayak and
Mr. Prasanna, Department of Pharmacology for their constant support and
encouragement.
Thanks to Mr. Rajaram Shetty, Mr. Pradeep Hegade, Mr. Shashidhar
rai, Mr. Ravindranth Poonja, Mr.Balakrishna, Mr. Gururaj Mrs. Vidyavathi
Mrs. Jyothi Shetty, Mrs. Usha Kumari and Mr.Jagannath for their kind co-
operation and constant help.
Words cannot express my heartfelt appreciation to my ever loving,
affectionate, Beloved Daddy, Mummy, Nilafoi, brother Niketan, sister Vidita and
all other family members for their life time support, everlasting love,
encouragement and prayers without which I would not have achieved my goal
I would like to convey my special thanks and deep sense of gratitude to my
beloved “Daddy” because of whom, I stand where I am today.
Words cannot express my heartfelt gratitude and special thanks to my
Beloved husband Kinjal, Father-in-law, Mother-in-law and all other family
members for their everlasting love prayers and encouragement in carrying out my
work.
I specially convey my gratitude to all my friends Raghav, Brijesh, Vipin,
Gunjan, Kantharaj, Srikanth, Jignesh, Santosh, Vimal, Venkatesh, Ashish,
Paro, Nirmala, Abinash, Amit, Nimesh and all my senior friends. I would like to
appreciate their moral support and concern shown to me.
I specially convey my thanks to Uncle, Aunty, Saloni, Nikita, Pratiksha
and Urvashi for their constant encouragement and love.
I would like to convey my special thanks to the staff of Saraswati
Graphics for their fast and efficient work.
Finally, I take the privilege to express my sincere thanks to one and all for
their affection and best wishes for the successful completion of this work.
Date:
Place: Mangalore Patel Ruchita Girishchandra
COPYRIGHT
I hereby declare that the Rajiv Gandhi University of Health Sciences,
Karnataka shall have the rights to preserve, use and disseminate this
dissertation/ thesis in print or electronic format for academic/ research
purpose.
Date : Place : Mangalore Ms. Patel Ruchita Girishchandra © Rajiv Gandhi University of Health Sciences, Karnataka
Rajiv Gandhi University of Health Sciences, Karnataka
Declaration
I hereby declare that the matter embodied in the dissertation entitled “COMPARISON
OF IN-VITRO RELEASE PROFILE OF DICLOFENAC FROM VARIOUS
FORMULATIONS” is a bonafide and genuine research work carried out by me
under the guidance of Mr. Sreedharan., M. Pharm, Assistant Professor, Department
of Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, Mangalore.
Date :
Place : Mangalore
Patel Ruchita Girishchandra
Table of Contents
Topic name P a g e N o .
Abstract i - i i
List of tables iii
List of figures iv
List of abbreviations v
Chapter - 1
Introduction 1-6
Chapter - 2
Objective 7-8
Chapter - 3
Review of Literature 9-21
Chapter - 4
Methodology 22-31
Chapter - 5
Results and Discussion 32-64
Chapter - 6
Summary
65-66
Chapter -7
Conclusion 67-68
Chapter - 8
Bibliography 69-73
Abstract
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. i
ABSTRACT
The objective of this study is to prepare calcium salts of diclofenac, and
evaluating its release property from conventional and matrix tablets and compare it
with the release property of diclofenac sodium from conventional and matrix tablets
in order to produce sustained effect of diclofenac. Calcium salt of diclofenac was
prepared by precipitating from the solution of diclofenac sodium by adding of calcium
chloride solution. Alginate matrix of diclofenac was prepared using ionic gelation
method (using 2%CaCl2 solution), then matrix was dried and evaluated for its
entrapment efficiency and compressed into tablets by direct compression method. The
tablets were subjected to thickness, weight variation, drug content, hardness,
friability, and in-vitro release studies. All the tablet formulations showed acceptable
pharmacotechnical properties. The USP paddle method was selected to perform the
dissolution, in 900ml of pH7.2 phosphate buffer. Diclofenac calcium from
conventional tablets showed slow release up to 6 hours compared to diclofenac
sodium, released in 1 hour. This may be due to the better solubility of sodium salt
compared to the calcium salt and was found to be suitable for sustained release
formulation. Diclofenac sodium matrix tablets of ratio 1:2 (drug: alginate) exhibited
slow release (98% of the drug release in 8 hours) and was found to be suitable for
sustained release formulation, which was not possible with the matrix tablets of
diclofenac calcium, since it released the drug at much faster rate in 3 hours. IR spectra
revealed that there is a mixture of diclofenac sodium and diclofenac calcium in
alginate matrix. Though on the basis of solubility profile, the release of diclofenac
sodium was expected to be faster compared to calcium salt, released at much slower
rate from matrix tablet. Since calcium is a divalent ion there may be a complex
formation between alginate, diclofenac calcium and believed to be responsible for the
Abstract
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. ii
slow release of drug. The drug content in all the formulations remained within the
limits when stored at different temperatures. The best-fit release kinetics was achieved
with zero-order plot followed by Higuchi equation. It was concluded from the study
that, diclofenac calcium might be used as sustained release salt. Compared to
conventional tablets of diclofenac sodium, release of diclofenac calcium from
conventional tablets and diclofenac sodium from matrix tablets was prolonged.
Keywords: Sustained release, Diclofenac sodium, Sodium alginate, Calcium chloride,
and Matrix tablet.
iii
List of Tables
Sl. No Tables Page No.
Table 1: List of retardant material used in the matrix. 3
Table 2: Composition of conventional tablet. 25
Table 3: Quantity of drug and polymer used in the preparation of matrix. 26
Table 4: Composition of matrix tablet. 27
Table 5: Standard calibration data of diclofenac sodium in phosphate buffer pH 7.2.
32
Table 6: Solubility of diclofenac sodium and diclofenac calcium in distilled water.
34
Table 7: Percentage yield of diclofenac in matrix of sodium alginate. 34
Table 8: Drug content in matrix. 35
Table 9: Physical properties of tablets. 38
Table 10: Drug content of tablets. 38
Table 11: Dissolution data of F1 (Conventional tablets of diclofenac sodium).
39
Table 12: Dissolution data of F2 (Conventional tablets of diclofenac calcium).
39
Table 13: Dissolution data of F3 (Diclofenac sodium matrix tablets 1:1). 41
Table 14: Dissolution data of F4 (Diclofenac sodium matrix tablets 1:2). 42
Table 15: Dissolution data of F5 (Diclofenac calcium matrix tablets 1:1). 43
Table 16: Dissolution data of F6 (Diclofenac calcium matrix tablets 1:2). 44
Table 17: Dissolution data of Voveran – 50 (Conventional tablet). 49
Table 18: Dissolution data of Nac – 50 (Conventional tablet). 49
Table 19: Dissolution data of Voveran SR – 100 (Sustained release tablet). 50
Table 20: Dissolution data of Divon SR – 100 (Sustained release tablet). 51
Table 21: Comparison of regression co-efficient values for different formulations.
60
Table 22: Regression co-efficient values of different formulation for higuchi plot.
60
Table 23: Percentage drug content of formulations F3 and F4 under different temperature conditions.
63
Table 24: Percentage drug content of formulations F5 and F6 under different temperature conditions.
64
iv
List of Figures
Sl. No Figures Page No.
Fig 1 Release of drug from matrix diffusion controlled drug delivery system.
5
Fig 2 UV absorption spectra of diclofenac sodium. 32
Fig 3 Calibration curve of diclofenac sodium in phosphate buffer pH 7.2 at 276 nm.
33
Fig 4 UV absorption spectra of diclofenac sodium in alginate matrix.
36
Fig 5 UV absorption spectra of diclofeance calcium. 36
Fig 6 UV absorption spectra of diclofeance calcium in alginate matrix.
37
Fig 7 Comparative dissolution profile of formulation F1 and F2. 40
Fig 8 Comparative dissolution profile of formulation F3 and F5. 44
Fig 9 Comparative dissolution profile of formulation F4 and F6. 45
Fig 10 Comparative dissolution profile of formulation F2 and F5. 47
Fig 11 Comparative dissolution profile of marketed conventional tablets and F1 and F2.
52
Fig 12 Comparative dissolution profile of marketed sustained release tablets and F2 and F4.
52
Fig 13 Comparative dissolution profile of F3 and F4. 54
Fig 14 Comparative dissolution profile of F5 and F6. 54
Fig 15 IR spectra of sodium alginate. 55
Fig 16 IR spectra of diclofenac sodium. 56
Fig 17 IR spectra of diclofenac sodium in alginate matrix. 57
Fig 18 IR spectra of diclofenac calcium. 58
Fig 19 IR spectra of diclofenac calcium in alginate matrix. 59
Fig 20 Higuchi plot of F3 61
Fig 21 Higuchi plot of F4 62
Fig 22 Higuchi plot of F5 62
Fig 23 Higuchi plot of F6 63
v
List of Abbreviations
% = Percent
°C = Degree Celsius
gm = Gram
ml = milliliter
nm = nanometer
mg = Milligram
Cm = Centimeter
min = Minutes
hrs = Hours
rpm = Rotations per minute
w/v = Weight per volume
v/v = Volume per volume
w/w = Weight by weight
λ max = Absorption maxima
µg/ml = Microgram per milliliter
conc = Concentration
SD = Standard deviation
DF = Dilution factor
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 1
INTRODUCTION
Controlled release drug delivery systems:1
For many decades treatment of an acute disease or chronic illness has been
accomplished by using various pharmaceutical dosage forms like tablets,
suppositories, ointments, etc. To maintain the drug concentration within the
therapeutically effective range, it is often necessary to take the dosage form several
times a day which may result in significant fluctuations in drug blood levels.
Recently several technical advancements have been made which are capable
of controlling the rate of dug delivery, sustaining the duration of therapeutic activity
and/or targeting the delivery of drug to a tissue. There are a variety of drug
modifications and dosage forms which are attempted to control the time course and
specificity of dugs in the body.
They are identified by various names such as controlled release/ sustained
release/ prolonged release and timed release etc.
The term-controlled release implies a predictability and reproducibility in the
release kinetics. This means that the release of drugs from the delivery systems
proceeds at a rate profile that is not only predictable kinetically but also reproducible
from one unit to another.
In general controlled drug delivery attempts to:2
1) Sustain drug action at a predetermined rate by maintaining a relatively
constant, effective drug level in the body with concomitant minimization of
undesirable side effects associated with a saw tooth kinetic pattern.
2) Localize drug action by spatial placement of a controlled release system
adjacent to or in the diseased organ or tissue.
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 2
3) Targeting drug by using carriers or chemicals and to a particular target cell
type.
Rationale for Controlled Drug Delivery:2
Basic rationale for Controlled Drug Delivery is to alter the pharmacokinetics
and pharmacodynamics of pharmacologically active moieties by using novel drug
delivery systems or by modifying the molecular structure and/or physiological
parameters inherent in a selected route of administration. It is desirable that the
duration of action becomes more a design property of a rate-controlled dosage form
and less or not at all, a property of the drug molecules inherent kinetic properties.
Presently the majority of these systems are based on polymers that differ in
degree of erodability, swellability and sensitivity to the biological environment in
which they are placed5.
Matrix Tablets:3,4
Matrix technologies have often proven popular among the oral controlled drug
delivery technologies because of their simplicity, ease in manufacturing, high level of
reproducibility, stability of raw materials and dosage form, and ease of scale –up and
process validation. Technological advancement in the area of matrix formulation
have made controlled release product development much easier than before, and
improved upon the feasibility of delivering a wide variety of drugs with different
physicochemical and biopharmaceutical properties. This is reflected by the large
number of patents filed each year and by the commercial success of a number of
novel drug delivery system based on matrix technologies.
Matrix based delivery technologies have steadily matured from delivering
drugs by first order or square root of time release kinetics to much more complex and
customized release patterns. In order to achieve linear or zero order release, various
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 3
strategies that seek to manipulate tablet geometry, polymer variables, and formulation
aspects have been applied. Various drug, polymer and formulation related factors,
which influence the in-situ formation of polymeric gel layer/drug depletion zone and
its characteristics as a function of time, determine the drug release from matrix
systems.
One of the least complicated approaches in the manufacture of sustained
release dosage form involves the direct compression of blends of drug, retardant
material (lipophilic or hydrophilic) and additives to form a tablet in which drug is
embedded in a matrix core of retardant.
Table 1:List of retardant material used in matrix tablet.
Matrix characteristics Material
Insoluble, inert Polyethylene, Polyvinyl chloride, Methyl
acrylate-methacrylate co-polymer, Ethyl
cellulose
Insoluble, erodible Carnauba wax
stearyl alcohol
stearic acid
polyethylene glycol
Castor wax
polyethylene glycol monostearate
Trigrycerides.
Hydrophilic Methyl cellulose (400 cps, 4000 cps)
Hydroxy ethyl cellulose, Hydroxy
propylmethyl cellulose (60HG, 90HG, 25
CPS, 40000 CPS, 15000 CPS), Sodium
carboxy methyl cellulose, Carboxy
polymethylene, Sodium alginate
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 4
Tablets prepared from the first class of polymers are designed to be ingested
intact and do not break apart in the GI tract. The rate- limiting step in controlling
release from these formulations is liquid penetration into the matrix unless channeling
(wetting) agents are included to promote penetration of the polymer matrix by water,
which allows drug dissolution and diffusion from the channels, created in the matrix.
Tablets prepared from the second class of materials control the release of drug
through both pore diffusion and erosion. Release characteristics are therefore more
sensitive to digestive fluid composition than to totally insoluble polymer matrix.
Third group of matrix formers represents non-digestible materials that form
gels in situ. Drug release is controlled by penetration of water through a gel layer
produced by hydration of the polymer and diffusion of drug through the swollen,
hydrated matrix in addition to the erosion of the gelled layer. The extent to which
diffusion or erosion controls the release, depends on the polymer selected for the
formulation as well as on the drug polymer ratio.
Alginates are established among the most versatile biopolymers, used in the
wide range of application. Hydrocolloids like alginate play a significant role in the
design of controlled release product. At low pH hydration of alginic acid leads to the
formation of high viscosity “acid gel”. Alginate is also readily gelled in the presence
of divalent cation such as calcium ion. Dried sodium alginate reswells creating a
diffusion barrier and thereby decreasing the migration of molecules (e.g.: -drugs).
Ability of alginate to form two types of gel dependant on pH i.e., an acid gel and an
ionotropic gel, gives the polymer unique properties compared to neutral
macromolecules.6
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 5
Matrix Diffusion Controlled Drug Delivery System:7
Drug dispersion in the polymer matrix is accomplished by (i) blending the
dose of finely powdered or ground drug particles with a viscous liquid polymer or a
semisolid polymer, followed by cross-linking of polymer chains or (ii) by mixing
drug solids with a melted polymer at an elevated temperature. The resultant drug-
polymer dispersion is then molded or extruded to form devices of various sizes and
shape.
Rate of drug release from matrix diffusion controlled drug delivery systems is
time dependent as defined by
= -
A is the loading dose of drug initially dispersed in polymer matrix.
CR is drug solubility in polymer.
Dp is diffusivity of drug molecules in the polymer matrix.
dQ dt
A CR DP 1/2
2t
Ch. 1Introduction
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 6
Fig 1: Release of drug from matrix diffusion controlled drug delivery system with
drug reservoir exist as homogenous dispersion in a) lipophilic, non-swellable polymer
matrix with growing thickness of drug depletion zone or b) Hydrophillic, swellable
polymer matrix with growing gel.
SALT FORM OF THE DRUG AND ITS ABSORPTION:8,9
Salt formation is frequently performed on weak acidic or basic drugs because
it is relatively simple chemical manipulation, which may alter the physicochemical,
formulation, biopharmaceutical, and therapeutic properties of a drug without
modifying the basic chemical structure.
Ideal characteristics of a salt are chemically stable, non-hygroscopic, present
no processing problems, dissolves quickly from solid dosage forms or dissolves
slowly if it is formed with the intent to delay dissolution and exhibits good
bioavailabilty.
Drugs that are administered orally and are sensitive to acid environments
benefits from forming salts which are poorly soluble in acidic condition.
Bioavailability of magnesium and calcium salts of indomethacin was
compared in rats for indomethacin. Mean plasma levels after single oral dose of salts
were significantly higher and the area under the plasma curve after multiple oral
dosing of salts was significantly higher than the administration of indomethacin free
acid.
Calcium salts of drugs can results in higher melting points and perhaps lower
solubility and higher chemical stability. Calcium salts are usually less hygroscopic
than sodium salts and exhibit a characteristic negative heat of solution.
Potassium salt of penicillin yields a higher peak concentration of antibiotic in
plasma than does the free acid. Oral administration of the calcium salt yields peak
plasma levels intermediary to those of sodium salt and free acid.
Ch. 2 Objectives
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 7
Need for the study:
Diclofenac sodium is an non-steroidal anti- inflammatory drug (NSAID), used
for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal
injury and dysmenorrhea. It is administered in dose of 75-100mg per day in 3-4
divided doses. It has short biological half life of 1-2 hours and is eliminated rapidly.
So multiple dosing is required to maintain required therapeutic level. Frequent
administration results in peaks and trough in drug blood level leading to erractic
plasma level.
Besides this most frequent side effects occurring with diclofenac are gastro
intestinal disturbances, peptic ulceration and gastrointestinal bleeding, which may be
appreciable on long term administration with multiple dosing. Based on these
drawbacks, it is necessary to develop sustained release formulation. There has been no
study that investigates the sustained release property of calcium salts of diclofenac.
The poor solubility of calcium salt in general, by itself would impart sustained release
character of molecule.
Alginate has been chosen as matrix forming material for formulating sustained
release dosage form, as it was reported that the release of sodium salt of diclofenac
reduces drastically from alginate due to complex mechanisms. Hence the present
study was undertaken to study the sustained release behaviour of diclofenac from
alginate.
In the present work an attempt was made to prepare calcium salts of
diclofenac and evaluate its release property from conventional and matrix tablets and
to compare it with release study of diclofenac sodium from conventional and matrix
tablets.
Ch. 2 Objectives
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 8
× Objective of the study
The objectives of the present present study are to:-
1. Prepare calcium salt of diclofenac.
2. Analyze qualitatively the formation of diclofenac calcium salt.
3. Formulate conventional tablets of calcium diclofenac and sodium diclofenac.
4. Prepare matrix tablets of above salts with sodium alginate.
5. Evaluation of the above prepared tablets.
Eg: Shape, thickness, weight variation, friability, hardness and tablet content.
6. Evaluate the in-vitro drug release study.
7. Evaluate the Stability studies.
8. Comparative study of drug release pattern for both conventional and matrix
tablets of diclofenac sodium and diclofenac calcium with marketed sustained
release tablets of diclofenac as well as conventional tablets.
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 9
REVIEW OF LITERATURE
Drug profile:10,11,12,13
Diclofenac sodium:
Molecular formula:- C14H10O2Cl2N Na
Molecular weight: - 318.13
Chemical name :-2-[(2, 6-dichlorophenyl)-amino] phenyl acetate.
Description: - white to slightly yellowish crystalline powder, slightly hygroscopic.
Solubility:-
Freely soluble in methanol, soluble in ethanol (95%), sparingly soluble in
water and glacial acetic acid, practically insoluble in ether, chloroform and toluene.
Melting point :-
Melts at about 280°c with decomposition.
Standards :-
Diclofenac sodium contains not less than 98.5% and not more than 101.0% of
C14H10Cl2N NaO2, calculated with reference to the dried sample.
Pharmacological properties:-
Diclofenac has analgesic, antipyretic and anti- inflammatory activities. It is a
potent relatively non-selective cyclooxygenase inhibitor and its potency is greater
than that of indomethacin naproxen, or several other agents. In addition, diclofenac
appears to reduce intracellular concentration of free arachidonate in leucocytes,
perhaps by altering the release or uptake of the fatty acid.
Pharmacokinetics:-
Diclofenac is rapidly and completely absorbed after oral administration; peak
concentrations in plasma are reached within 2-3 hours. Administration with food
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 10
slows the rate but does not alter the extent of absorption. There is a substantial first-
pass effect, such that only about 50% of diclofenac is available systemically. The
drug is extensively binds to plasma proteins (99%) and its half- life in plasma is 1-2
hours. Diclofenac accumulates in synovial fluid after oral administration, which may
explain the duration of therapeutic effect that is considerably longer than the plasma
half- life. Diclofenac is distributed into breast milk but the amount is considered by
some authorities is to be too small to be harmful to breast fed infants.
Metabolism:-
Diclofenac is metabolized in Liver by a cytochrome P-450 isozyme of the
CYP2C sub family to 4-hydroxy diclofenac, the principal metabolite and other
hydroxylated forms; after glucuronidation and sulfation. The metabolites are excreted
in the urine (65%) and bile (35%). Biliary clearance can account for up to 30% of
total clearance.
Therapeutic uses:-
Diclofenac sodium is used for the long-term symptomatic treatment of
rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. Also useful for short-
term treatment of acute musculoskeletal injury, acute painful shoulder (bicipital
tendinitis and subdeltoid bruisitis), post-operative pain and dysmenorrhoea.
Adverse Effects:-
Occur in approximately 20% of patients and include gastro- intestinal distress,
gastro- intestinal bleeding and gastric ulceration. Elevation of hepatic amino-
transferase activities in plasma occurs in about 14% of patients. Other untoward
responses to diclofenac include CNS effects, skin rashes, allergic reaction, fluid
retention and edema, and rarely impairment of renal function.
Dosage:-
75-150mg daily in divided doses.
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 11
Polymer profile:
Sodium alginate:14
Synonym: Manugel, Sodium polymannuronate,
Chemical name : - Sodium alginate.
Functional category :
Stabilising agent, suspending agent, tablet and capsule disintegrant, tablet
binder and viscosity increasing agent.
Application in pharmaceutical formulation:
Sodium alginate is mainly used in a variety of oral and topical pharmaceutical
formulation. In tablet formulation, sodium alginate can also be used in preparation of
sustained release oral formulation since it can delay the dissolution of a drug from the
tablets.
Description: -
Sodium alginate occurs as an odorless and tasteless, white to pale yellowish
brown colored powder.
Solubility:-
Practically insoluble in ethanol, ether and ethanol/water mixtures in which the
ethanol content is greater than 30%. Also practically insoluble in other organic
solvents and acids in which the pH of the resultant solution is less than 3. It is readily
soluble in water forming a viscous colloidal solution.
Viscosity: -
A 1% w/v aqueous solution at 20° will have a viscosity of 20-400cps.
Viscosity varies depending on concentration, pH, temperature or presence of metal
ions. Above pH 10, viscosity reduces.
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 12
Stability and storage: -
Sodium alginate is a hygroscopic material. It is stable if stored at relatively
low humidities and cool temperature. Aqueous solution of sodium alginate is most
stable between pH 4-10. Below pH 3, alginic acid gets precipitated. Sodium alginate
is susceptible to microbial spoilage on storage, which may affect solution viscosity.
Safety: -
It is non-toxic and non- irritant material.
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 13
Ø Bodmier et al (1989)15 studied the agglomeration of poorly water soluble drugs
like ibuprofen, indomethacin, micronised griseofulvin, sulphadiazine and
tolbutamide by dispersing each drug in chitosan or sodium alginate and then
dropping the dispersion into a solution of calcium chloride. The droplets
instantaneously formed gelled spheres by ionotropic gelation. The ionic character
of the polymer resulted in pH dependant disintegration of the beads like chitosan
disintegrated in acidic condition (0.1N HCl) and sodium alginate in intestinal pH.
Ø S. Malamataris and D. Ganderton (1991)16 studied the in-vitro release from the
matrix comprising hydrophobic and hydrophilic (gel- forming) components
containing three non-steroidal anti- inflammatory agents with different solubility
and wettability (indomethacin, ibuprofen and diclofenac sodium). Release rate
decreased with drug/matrix ratio for wettable, soluble diclofenac but increased
with indomethacin and ibuprofen. The release rate changes are explained on the
basis of the interaction between the gel and other matrix components in the
presence of water.
Ø Bain J. C et al (1991)17 investigated the in-vitro release characteristic of
diclofenac sodium from sustained release wax matrix and hydrogel tablet. The
wax matrix tablets exhibited classic diffusion controlled release of diclofenac
down tortuous pores and were relatively independent of rotational speeds when
the tablets were free from abrasion. The hydrogel tablet exhibited near zero order
release where a dynamic equilibrium exists between rate of swelling and erosion
up to a point where high rotation speeds upset this equilibrium by increasing
erosion.
Ø Lin S Y et al (1995)18 prepared and evaluated sodium diclofenac controlled
release tablets by using dibasic calcium phosphate (DCP) in different weight
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 14
ratios with or without biosoluble polymer (acrylic based resin) in distilled water
and in a medium with changing pH. The results indicate that the amount of
sodium diclofenac released from the compact was dependent on the amount of
drug and DCP used in the compact, and was also controlled by amount of
bisoluble polymer added. The tablet with a 1:2 weight ratio of sodium diclofenac
to DCP exhibited a sustained release behavior, similar to commercial sustained
release products (Voltaren SR – 100 and Grofenac retard), but a lower release rate
was found as compared to the commercial products.
Ø Alison C. Hodsdon et al (1995)19 studied the effect of pH and drug solubility on
the release kinetics of sodium alginate matrices. Release of a highly soluble model
drug, chloramphenicol maleate was significantly faster in simulated gastric fluid
(SGF) than in simulated intestinal fluid (SIF), whereas the opposite effect was
observed for hydrochlorthiazide, a drug of poor solubility. These results could be
explained in terms of the internal microscopic structure of the hydrated surface
layer formed on matrix hydration and by different hydration kinetics of the
polymer in these two media. Cryogenic electron microscopy revealed the hydrated
surface layer formed by alginate matrices in SGF to be particulate and porous in
nature, in contrast to highly hydrated continuous gel layer formed in SIF. Drug
release mechanisms were discussed with respect to drug solubility and the
structure and properties of the surface layers formed by alginate matrices when
hydrated in different pH media.
Ø Liu C. H. et al (1995)20 studied five controlled release matrix tablet formulation
containing diclofenac sodium and HPMC. They were prepared and evaluated in-
vitro and in 6 healthy male subjects who received the oral formulation in a cross-
over design. All the five formulations prolonged drug release in-vitro. The main
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 15
factors controlling release were the higher the concentration of high viscosity
grade polymer, the slower the release rate. There were in-vitro correlations
between the plasma Cmax, area under the plasma drug concentration time curve
and time for 50 to 80% drug to be released.
Ø Kikuchi et al (1997)21 prepared calcium alginate gel beads for pulsed dextran
release. They found that sodium alginate forms a hydrogel upon contact with
calcium ions in aqueous solution due to physical cross-linking (chelation) between
the carbohydrate anions of glucuronate units in alginate and the calcium ions.
Alginate disintegration (dissolution) in phosphate buffered saline solution (pH 7.4)
occurs completely in a short time period after a certain lag time. Calcium ions
release from the alginate gels is believed to be an influential factor in alginate
dissolution. The larger the diameters of the alginate beads, the slower the observed
release time onset. Furthermore, dextran release was in a pulsatile fashion using
calcium-alginate gel beads by mixing different bead sizes. These results indicate
that pulsatile release of macromolecular drugs such as proteins and peptides could
be achieved using calcium alginate beads.
Ø Takagi I et. al., (1997)22 studied the possibility of producing calcium induced
alginate beads as a vehicle for liposomes was explored. The liposomes were well
maintained within both fully cured and washed beads. The liposome release from
the fully cured beads was much slower than that from the corresponding washed
beads in a pH 7.4 releasing medium. The greater the liposome loading, the faster
the release of the vesicles. The liposome release was investigated in terms of
liposome loading, swelling of the gel body, calcium discharge and gel erosion
using washed beads. The liposome loading did not affect the bead erosion or
calcium discharge but did the initial swelling ratio and liposome release. The
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 16
result suggests that the loaded liposomes are not uniformly distributed in the bead
but are rather gradually concentrated to the centre.
Ø Takka S. et al., (1998)23 prepared and studied the release rate of nicardipine HCl
from various alginate gel beads. The formulations were prepared by using
factorial design. The effect of drug: polymer weight ratio, calcium chloride and
sodium alginate concentration on the time for 50% of the drug release and the
entrapment efficiency were evaluated with analysis of variance. The mean particle
size and the swelling ratio of the beads were determined. The in-vitro release
studies were carried out by flow through cell apparatus in different media. Release
of nicardipine was extended with the alginate beads, which were prepared in a
ratio of 1:1 (drug: polymer). The release of drug from alginate beads took place
both by diffusion through the swollen matrix and relaxation of polymer at pH 1.2-
4.5. The release was due to diffusion and erosion mechanism at pH 7-7.5.
Ø M.J. Fernandez-Hervas et al., (1998)36 formulated alginate beads containing
diclofenac hydroxyethylpyrolidine with either eudragit or chitosan in order to
achieve an enteric formulation. The examination of fractured beads revealed an
internal void in the eudragit-alginate beads. In contrast, a dense homogeneous
internal structure was observed in the chitosan-alginate beads due to
interpolymeric complex. An interaction between chitosan and drug was also
observed. Under conditions mimicking those in the stomach, a small amount of
drug was released. The alginate chitosan beads showed release behaviour
dependent on pH value and alginate chitosan ratio.
Ø Vines Pillay et al., (1999)34 investigated the cross- linking of sodium alginate, low
methoxylated pectin and their novel binary mixture with calcium ions through
ionotropic gelation to pelletize the model drug, diclofenac sodium using
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 17
“environmentally benign” solvents and processing techniques. Cross- linked
pellets of the above polymers in 2% (w/v) aqueous calcium chloride solution were
prepared and evaluated for their structural and release behavior. Negligible drug
release occurred in pH 1-4. However, rate of drug release in pH 6.6 ranged from
rapid to slow but always in a controlled manner.
Ø Anandrao R Kulkarni et al., (1999)35 prepared controlled release sodium alginate
(Na-Alg) beads containing diclofenac sodium (DS) by precipitation of Na-Alg in
alcohol followed by cross-linking with glutaraldehyde (GA) in acidic medium.
Beads were optimized by considering the percentage entrapment efficiency,
swelling capacity of beads in water and their release data. The beads produced at
higher temperatures and longer times of exposure to the cross- linking agent have
shown the lower entrapment efficiency, but extended release of DS from the
beads. The scanning electron microsopic studies indicated nonporous smooth
surfaces and the differential scanning calorimetric data indicated the molecular
level dispersion of the drugs in the beads.
Ø Paolo Giunchedi et al., (2000)24 investigated the use of sodium alginate for the
preparation of hydrophilic matrix tablets intended for prolonged drug release
using ketoprofen. Matrix tablets were prepared by direct compression using
sodium alginate, calcium gluconate and hydroxylpropylmethylcellulose (HPMC)
in different combinations and ratios. Matrices consisting of sodium alginate alone
or in combination with HPMC gave a prolonged drug release at a fairly constant
rate. Incorporation of different ratios of calcium gluconate leads to an
enhancement of the release rate from the matrices and loss of constant release rate
of the drug.
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 18
Ø Bravo S A. et al., (2002)25 prepared uncoated HPMC matrix tablets and evaluate
the relationship and influence of different content levels of microcrystalline
cellulose (MCC), starch and lactose in order to achieve zero order release of
diclofenac sodium and found that the release of diclofenac sodium and found that
the release of diclofenac sodium was influenced by the presence of MCC and by
different concentration of starch and lactose. The release of drug from HPMC
matrix tablets was prolonged when compared to conventional diclofenac tablets.
Ø M.L. Gonzalez-Rodriguez et al., (2002)37 prepared alginate chitosan particles by
ionic gelation (Ca2+ and Al3+) for the sodium diclofenac release. The systems were
characterized by electron microscopy and differential scanning calorimetry. The
ability to release the active substance was examined as a function of some
technological parameters and pH of dissolution medium. The release of sodium
diclofenac is prevented at acidic pH, while is complete in a few minutes when pH
is raised up to 6.4 and 7.2. The alginate/chitosan ration and the nature of the
gellifying cation allow a control of the release rate of drug.
Ø AL- Taani B M. et al., (2003)26 studied the effect of microenvironment pH on the
release pattern of diclofenac sodium from pH dependant swellable and erodible –
buffered matrices and found that the rate of drug release is increased with the
increase of the micro-environment pH of matrices but the release pattern of drug
was unaffected.
Ø Maria Luisa Gonzalez – Rodriguez et al., (2003)27 designed delivery system
consisted in a polymeric matrix tablet containing a drug central core for obtaining
a time controlled release profile characterized by an initial phase of lag time
followed by a controlled release phase according to zero order kinetics. Eudragit
RS 100 was used as inert polymeric matrix for the core coating, mixed with
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 19
sodium chloride and emdex as channeling agent. Lag time increased with
decreasing the channeling agent particle size. Formulation containing sodium
chloride always showed longer lag times than corresponding with emdex and were
more effective in providing prolonged zero-order release periods. By varying the
sodium chloride/eudragit w/w ratio it was possible to suitably modulate the length
of both the lag time (for achieving colonic targeting) and zero order release
phases.
Ø Holte A. et al., (2003)28 investigated the release of acetyl salicylic acid from
directly compressed alginate tablets. The effect of the amount and type of alginate
on the drug release rate was evaluated in different formulations. Four different
grades of alginates were used. Drug release sustained up to 16 hour was achieved
using sodium alginate in combination with dibasic calcium phosphate.
Ø S. S. Biju et al., (2004)29 formulate novel enteric micro-capsules for improved
delivery to the intestine using the polymers cellulose acetate phthalate (CAP) and
ethyl cellulose (EC) of diclofenac sodium. In-vitro release study was carried out
in simulated gastric fluid for first 2 hour and simulated intestinal fluid for next 6
hour. Best formulation that contains CAP and EC in the concentration of 10:90 at
1:1.5 drug: polymer ratio was further evaluated using in-vivo for its
pharmacodynamic efficacy and ulcerogenicity. In addition to sustained and
uniform release of drug, the formulation showed better anti- inflammatory activity
than marketed formulation and retarded drug release in the gastric medium. The
biological examination of incised stomach showed no histological alterations in
terms of mucous surface cells and glands.
Ø Ali Nokhodchi et al., (2004)30 investigated matrices of calcium alginate or
aluminum alginate as possible controlled release system for drugs. Objective of
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 20
the study was to sustain the release of theophylline from alginate matrices using
different concentration of aluminum chloride and calcium chloride in presence
and absence of HPMC. Tablets containing differing concentration of aluminum
and calcium chloride were produced & the release rate of theophylline was tested.
Increasing the amount of aluminum chloride, decreased the release of theopylline
indicating a significant effect of aluminum ions on a reduction in the release rate
of theophylline from alginate matrices. In case of matrices containing different
concentration of calcium ions, as the concentration of calcium chloride increases,
the release rate increased to an optimum then declined after this. This was due to
insufficient calcium ions being available to cross-link with the sodium alginate to
form an insoluble gel. The results also showed that the presence of HPMC cause
a reduction in release rate of theophylline from alginate matrices. Whereas, in case
of alginate matrices containing aluminium chloride the release rate of theophylline
increased in presence of HPMC.
Ø Bravo S. A. et al., (2004)31 investigated the delivery of drugs by a process of
continuous swelling of the polymeric carrier for oral sustained release systems.
The goal of the study was to evaluate the effects of HPMC and carboxy polymer
(carbopol 934) on the release behaviour of diclofenac sodium (DS) from a
swellable matrix tablet system. The influence of the polymer content, the polymer
ratio, the polymeric swelling behavior and the pH changes on the release rate of
DS was investigated. There was no significant difference in drug release when
total polymer concentration was 10%. When the tablets were formulated having
20% or 30% of HPMC/cabomer, it was observed that a more rapid release of DS
occurred as carboxy polymer ratio within the matrices increased. The dissolution
studies demonstrated that the combination of these two polymeric matrix formers
Ch. 3 Review of Literature
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 21
resulted in near zero-order release rate of DS. The DS release from all these
matrix tablets was pH dependant.
Ø Ayhan Savaser et al., (2005)32 studied the effect of formulation variables on the
release profile of diclofenac sodium from hydroxypropylmethylcellulose (HPMC)
and chitosan matrix tablets. In-vitro studies showed that 20% HPMC contained
sustained release formulation with direct compression method is the optimum
formulation due to its better targeting profile in terms of release. This formulation
also exhibits the best-fitted formulation in zero order kinetics.
Ø Satit Puttipipathachorn et al., (2005)33 prepared diclofenac calcium-alginate
(DCA) beads with different amounts of sodium starch glycolate (SSG) or
magnesium aluminium silicate (MAS) using ionotropic gelation method.
Complex formation of sodium alginate and SSG or MAS in calcium alginate
beads was revealed using FT-IR spectroscopy. Thermal behavior of SSG- DCA
and MAS-DCA beads was similar to the control beads. Both additives can
improve the entrapment efficiency of DCA beads. The swelling and water uptake
of the beads depend on the properties of incorporated additives. Release kinetics
of the beads was swelling controlled mechanism in phosphate buffer pH 6.8, while
that in distilled water fo llowed Higuchi’s model.
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 22
MATERIALS
Drug
Diclofenac sodium J.B. Chemicals. Mumbai
Polymers
Sodium alginate Glenmark Pharmaceuticals Ltd.
Chemicals
Calcium chloride E.merck, Mumbai
Sodium hydroxide Merck, Mumbai
Potassium dihydrogen phosphate Genuine chemical Co., Mumbai
Oxalic acid Nice chemicals, Cochin
All the other chemicals used were of analytical reagent grade. (A. R. grade)
Eqiupments
UV/visible spectrophotometer Jasco V-530
Desiccator Terrasons
Hot air oven Kemi, KUHS-2
Electronic balance Ohasus Corporation, Japan
Tablet dissolution tester USP(XXIII) Electrolab
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 23
METHODOLOGY
Preparation of 0.2M potassium dihydrogen phosphate solution: -
27.218gm of potassium dihydrogen phosphate was dissolved in distilled water
and diluted with distilled water to 1000ml.
Preparation of 0.2M sodium hydroxide solution: -
Dissolved 8gm of sodium hydroxide in distilled water and diluted with
distilled water up to 1000ml.
Preparation of phosphate buffer pH 7.2: -
Placed 50.0ml of 0.2M potassium dihydrogen phosphate in a 200ml
volumetric flask, and 34.7ml of 0.2M sodium hydroxide solution was added and
distilled water was added up to the volume to make 200ml.
Preparation of standard stock solution in phosphate buffer pH 7.2: -
100mg of pure drug diclofenac sodium was accurately weighed and
transferred into a 100ml volumetric flask. Small quantity of buffer was added and
dissolved. Volume was made up to 100ml using phosphate buffer pH 7.2. (Stock
solution -1000µg/ml of drug).
4.1. Scanning of diclofenac sodium:
From the above stock solution suitable quantity was withdrawn and the
volume was made up to 100ml with phosphate buffer to get a concentration of
10µg/ml and the sample was scanned between 250-350nm as shown in fig 2.
4.2. Preparation of calibration curve: -
From the standard stock solution, secondary stock solution was prepared by
diluting the primary stock solution ten times so that the secondary stock solution with
a concentration of 100µg/ml. From this secondary stock solution, aliquots of 0.5ml to
2.5ml were transferred into a series of 10ml volumetric flasks and final volume was
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 24
made up with buffer to give the concentration ranging from 5µg/ml to 25µg/ml. The
absorbance of these solutions was measured against a phosphate buffer pH 7.2 as a
blank in UV/visible spectrophotometer at 276nm. Average of three determinations
was taken. The data and the standard graph are shown in table 5 and fig 3
respectively.
4.3. Preparation of calcium salts of diclofenac: -
1gm of diclofenac sodium was dissolved in 100ml of distilled water. 7.5
mmoles of calcium chloride solution was prepared and added to the above solution
drop wise till the complete precipitation formed. Then the precipitate was filtered,
washed with distilled water and dried in hot air oven.
4.3.1 Confirmatory tests for the presence of calcium salts of diclofenac: -
i UV scanning : - The sample was dissolved in phosphate buffer pH 7.2 and
scanned between 200-300nm.
ii Calcium oxalate test38: - The salt was dissolved in water and added to
oxalic acid solution. There should be a formation of white precipitate of
calcium oxalate.
iii Flame test38: - The salt was dispersed in 0.1N HCl solution and was held
over Bunsen flame.
4.4. Solubility determination:
The solubility measurements of diclofenac sodium and diclofenac calcium
were investigated by adding an excess of drugs to the distilled water. After the
equilibrium was reached, the drug concentration in the supernatant was determined
spectrophotometrically. The results of the solubility measurements are given in
table 6.
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 25
4.5. Preparation of conventional tablets of Diclofenac sodium and Calcium salts
of diclofenac: -
Tablets were prepared by direct compression method. All the ingredients were
blended together in a bottle by tumbling action. Sodium starch glycolate was used as
disintegrant, lactose as diluent and magnesium stearate as lubricant. Powder mass was
compressed into tablets using a cadmach single punch tablet press with 6mm punch
and die set. Each tablet contains 100mg of diclofenac. Composition of each tablet is
given in table 2.
Table 2: Composition of conventional tablet
Quantity used for each tablet (mg) Ingredients
F1 F2
Drug 50 50
Lactose 150 150
Sodium Starch Glycolate 10 10
Magnesium Stearte 4 4
Total Weight 214 214
F1 – Diclofenac Sodium
F2 – Diclofenac Calcium
4.6. Preparation of alginate matrix of diclofenac sodium and diclofenac calcium.
Sodium alginate (2gm) was dissolved in distilled water (100ml). Drug (1gm)
was dispersed in specified volume of 2% sodium alginate solution as specified in
table 3. To the drug polymer dispersion 2% calcium chloride solution was added drop
wise with gentle stirring to form the gel matrix. The gel matrix was filtered, washed
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 26
with water and dried at an ambient condition. Then pulverized and passed through
sieve.
Table 3: Quantity of drug and polymer used in preparation of matrix
Type of Matrix Drug :
Polymer
Amount of Drug and Polymer
used
1:1
1 gm of diclofenac sodium and
50 ml of sodium alginate (2%)
solution (which contains 1 gm
sodium alginate) Diclofenac sodium : Sodium Alginate
1:2
1 gm of diclofenac sodium and
100 ml of sodium alginate (2%)
solution (which contains 2 gm
sodium alginate)
1:1
1 gm of diclofenac calcium and
50 ml of sodium alginate (2%)
solution (which contains 1 gm
sodium alginate) Diclofenac calcium : Sodium Alginate
1:2
1 gm of diclofenac calcium and
100 ml of sodium alginate (2%)
solution (which contains 2 gm
sodium alginate)
4.6.1 Evaluation of the matrix: -
The prepared matrix was evaluated for the percentage yield, percentage
entrapment efficiency of the drug and drug content.
4.6.1.1 Percentage yield of the matrix: -
The percentage yield of the matrix was found out based on the dry weight of
the drug and polymer taken and the final weight of the matrix obtained. The results
are given in the table 7.
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 27
4.6.1.2 Drug content analysis of the matrix: -
The amount of drug entrapped in alginate matrix was estimated by transferring
accurately weighed 100mg of matrix in 100ml volumetric flask. Matrix was dissolved
and volume was made up to100ml with phosphate buffer pH 7.2. The solution was
diluted suitably and the absorbance of the diluted solution was determined using UV
spectrophotometer at 276nm. The amount of drug entrapped in the matrix was
calculated from dilution. The results are given in table 8.
4.6.1.3 UV scanning: -
The UV scanning of the solution of matrix containing diclofenac sodium and
diclofenac calcium in phosphate buffer pH 7.2 was done to verify the presence of
drug in matrix and also to check whether there is any interaction of the drug with
polymer. The results are shown in fig 3 and 5 respectively.
4.6.2 Preparation of matrix tablets: -
Matrix tablets were prepared with the drug: polymer ratio of 1:1 and 1:2. The
matrix was passed through sieve 20. Magnesium stearate was added as a lubricant.
Quantity of matrix equivalent to 100mg of drug was taken and mixed with
magnesium stearate in a bottle by tumbling action. Powder mass was compressed into
tablet using a cadmach single punch tablet press with 6mm punch and die set. Each
tablet contains 100mg of diclofenac. Composition of each tablet is given in table 4.
Table 4: Composition of diclofenac matrix tablet
Quantity used for each tablet, (mg) F 3 F 4 F 5 F 6 Ingredients 1:1 1:2 1:1 1:2
Diclofenac Sodium matrix 242 400 - -
Diclofenac Calcium matrix - - 214 355
Magnesium Stearte 2 4 2 3.5
Total Weight 246 404 216 358.5
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 28
4.7. Evaluation of tablets:39
i. Shape of tablets:-
Compressed tablets were examined physically for the shape of the tablet.
ii. Thickness: -
The thickness of tablet was determined with the help of vernier calipers. The
thickness variation was allowed in the range of + 5% of the size of the tablet. The
results are given in table9.
iii. Hardness:-
Hardness indicates the ability of the tablet to withstand mechanical shocks
while handling. The hardness of the tablets was determined using Monsanto hardness
tester. It is expressed in Kg/cm2. 5 tablets were randomly picked and hardness was
determined. The results are given in table9.
iv. Friability:-
Friability of the tablets was determined using Roche Friabilator. It is
expressed in percentage (%). Ten tablets were initially weighed (Winitial) and
transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes or
run up to 100 revolutions. The tablets were weighed again (Wfinal). The % friability
was then calculated by-
% Friability of the tablets less than 1% is considered as acceptable.
The results are given in table 9
F= Winitial - Wfinal x 100
Winitial
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 29
v. Weight Variation Test:-
Ten tablets were selected randomly from each batch and weighed individually
to check for the weight variation. U.S. Pharmacopoeia allows a little variation in the
weight of a tablet. The results are given in table 9. The following percentage
deviation in weight variation is allowed.
Average weight of a tablet Percentage deviation
130 mg or less 10
> 130 mg and < 324 mg 7.5
324 mg or more 5
vi. Drug content in tablets:-
The tablet was triturated to form a fine powder and transferred to a 100 ml
volumetric flask and dissolved in phosphate buffer pH 7.2 and was made up to the
volume to get stock solution. 1ml of this stock solution was taken in a 100ml
volumetric flask and diluted with phosphate buffer pH 7.2 and made up to the volume.
The absorbance of this solution was measured at 276nm using UV spectrophotometer.
(Jasco V-530) The drug content was estimated from the absorbance obtained. The
results are shown in table 10.
4.8. In-vitro dissolution study:25
In-vitro dissolution study of the tablets was carried out in USP dissolution
apparatus type-II, using 900ml of phosphate buffer pH 7.2 as a release medium
maintained at 37+ 0.5° C with 50 rpm. 5 ml of samples was withdrawn at specified
interval and filtered and diluted with phosphate buffer pH 7.2 and assayed
spectrophotometrically at 276 nm. The equal volume of fresh medium was
immediately replaced to maintain the dissolution volume constant. The amount of
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 30
drug release at each time interval was calculated from the absorbance of the samples.
Three trials were carried out. The percentage drug release was calculated and this
was plotted against function of time to find out pattern of drug release. The results are
given in table 11 to 20 and figure 7 - 14.
4.9 IR studies:
The pure drug, polymer and its formulations were subjected to IR spectral
studies.
4.10 Comparison with marketed sustained and conventional product
The promising formulations of diclofenac were compared with marketed
products for drug release profile.
Details of marketed products
Voveran – 50: Diclofenac sodium – 50mg
Nac – 50: Diclofenac sodium – 50mg
Voveran – SR – 100: Diclofenac sodium – 100mg, Sustained Released Tablets
Divon – SR – 100: Diclofenac sodium – 100mg, Sustained Released Tablets
4.11 Curve fitting analysis:39,25,40
To analyse the mechanism of the drug release rate kinetics of all the
formulations, the data obtained were fitted into zero order release rate kinetics and
into Higuchi model.
4.11.1 Zero order release rate kinetics:
To study the zero order release kinetics the release data were fitted to the
following equation.
F=K.t
Where ‘F’ is the fraction of drug release,
‘K’ is the release rate constant, and
‘t’ is the release time.
Ch. 4 Methodology
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 31
4.11.2 Higuchi release model:
To study the Higuchi release kinetics, the release data were fitted to the
following equation,
F=K .t1/2
Where, ‘F’ is the amount of drug release,
‘K’ is the release rate constant, and
‘t’ is the release time.
The regression coefficients values are given in table 21 and 22.
4.12. Stability studies of the tablets:25
Stability of a formulation can be defined as the time from date of manufacture
of the formulation until its chemical or biological activity is not less than a
predetermined level of labeled potency and its physical characteristics have not
changed appreciably or deleteriously.
Formulation and the development of a pharmaceutical product is not complete
without proper stability analysis, carried out on it to assess the physical and chemical
stability and the safety.
A general methodology for predicting stability is accelerated stability analysis,
which subjects the material to elevated temperatures.
Accelerated stability Analysis:
Two tablets from all the batches were wrapped in an aluminum foil and were
subjected to different conditions (room temperature, at 45°C and at 60°C
temperature). The samples were observed regularly at an interval of two week and
the samples were analysed for the amount of the drug remaining, by procedure
described in drug content analysis in tablets by using UV spectrophotometer. The
stability of the tablets was determined from the obtained data. The results are given in
table 23 and 24.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 32
5.1 UV Scanning:
The UV spectra for pure drug is shown in Fig. 2:
Fig.2: UV absorption spectra of diclofenac sodium.
The UV absorption spectra shows the absorption peak at 276nm, which corresponds
to the peak of pure drug diclofenac.
5.2 Calibration curve for diclofenac sodium:
The values of absorbance for the calibration curve of diclofenac sodium in
phosphate buffer pH 7.2 are given in Table 5.
Table 5: Standard calibration data of diclofenac sodium in phosphate
buffer pH 7.2
Sr.no. Concentration (µg/ml)
* Absorbance Standard deviation (+)
1 0 0 0
2 5 0.1571 0.0051
3 10 0.3304 0.0020
4 15 0.4952 0.0015
5 20 0.6941 0.0043
6 25 0.8210 0.0018
* Average of three determinations
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 33
C= K* A+B
C=Concentration of the sample
K=30.527
A=Absorbance
B=0.0512
Fig. 3: Calibration Curve of Diclofenac sodium in phosphate buffer pH 7.2 at
276 nm.
5.3 Preparation of calcium salts of diclofenac: -
Calcium salts of diclofenac were prepared by the procedure described in
methodology section.
5.3.1 Confirmatory test: -
1. UV scanning: -The ? max was found to be 275.8nm in pH 7.2 phosphate buffer.
(Fig. 5)
2. When the solution of diclofenac calcium was added to oxalic acid solution,
white precipitate of calcium oxalate was formed.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 34
3. Flame test of diclofenac calcium gave a yellow-red color flame, which
indicated the presence of calcium.
5.4 Solubility determinations :
Solubility of diclofenac sodium was found to be 0.852mg/ml in distilled
water.
Solubility of diclofenac calcium was found to be 0.7466mg/ml in distilled water.
Table 6: Solubility of diclofenac sodium and diclofenac calcium in distilled
water.
Drug Solubility in distilled water
mg/ml
Diclofenac sodium 0.852
Diclofenac calcium 0.746
5.5 Evaluation of matrix: -
5.5.1 Percentage yield of the matrix: -
The percentage yield of diclofenac matrix with different drug to polymer ratio
is shown in the Table 7.
Table 7: Percentage yields of diclofenac in matrix of sodium alginate.
Formulation Drug to polymer ratio Percentage yield
1:1 89.5% Diclofenac sodium: sodium alginate
(DS:SA) 1:2 80.25%
1:1 82.5% Diclofenac calcium: sodium alginate
(DC:SA) 1:2 78.5%
In both the formulation, the yield was found to be highest in the case of lowest
drug to polymer ratio. The percentage yield of matrix range from 78.5% to 89.5%.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 35
5.5.2. Estimation of drug content in the matrix: -
The drug content was estimated in the matrix and is shown in Table 8.
Table 8: Drug content in matrix.
Drug content
Formulation Ratio Theoretical
(mg)
Practical
(mg) Percentage drug content
1:1 50 41.35 82.70% DS: SA
1:2 33.33 25.022 75.07%
1:1 50 46.75 93.50% DC: SA
1:2 33.33 28.17 84.51%
The drug content in calcium alginate matrix was found to be ranging from
75% to 93%, in which diclofenac calcium matrix shows higher drug content while
diclofenac sodium matrix shows lower drug content. Probably during the washing
stage there is a loss of diclofenac sodium since it is better soluble in water compared
to diclofenac calcium.
5.5.3 UV scanning: -
The presence of peak at 276nm in the UV absorption spectrum of the prepared
matrix containing the drug (as shown in Fig 4 and 6) confirmed the presence of
diclofenac in matrix.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 36
Fig. 4: UV absorption spectra of diclofenac sodium in alginate matrix
Fig. 5: UV absorption spectra of diclofenac calcium
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 37
Fig. 6: UV absorption spectra of diclofenac calcium in alginate matrix.
5.6 Evaluation of formulated tablets: -
5.6.1 Shape of the tablets:
Physical examination of tablets from each formulation found to be circular
shape with no cracks.
5.6.2 Thickness:
Thickness of all tablets was found to be within the limit of + 5% of size of the
tablet and was uniform in all the batches. The results are given in Table 9.
5.6.3 Hardness:
The measured hardness of the tablets of each formulation range between 5 to
7.5 Kg/cm2. This ensures the good handling characteristics of all the formulations.
The results are given in Table 9:
5.6.4 Weight variation:
The average percentage weight variation for all the formulations was shown in
Table 9. All the tablets passed weight variation test as the average percentage weight
variation remained within the pharmacopoeial limits.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 38
5.6.5 Friability:
The percentage friability was less than 1% in all the formulation ensuring that
the tablets were mechanically stable. The results are given in Table 9:
Table 9: Physical properties of the tablets.
Formulations * Thickness (mm)
Hardness (kg/cm2)
Average % Weight Variation
% Friability
F2 3.20+0.075 5-6.5 1.232 0.373
F3 3.08+ 0.020 6-7 1.278 0.245
F1 3.42+0.040 5-6 1.159 0.372
F4 3.48+0.044 7-7.5 0.702 0.22
F5 3.44+0.054 6-7 1.689 0.317
F6 3.48+0.083 7-7.5 0.867 0.25
* Average of three determinations
5.6.6 Drug content in tablets: -
The amount of drug content in each tablet has been evaluated for all the six
formulation. From this study the drug content in all the tablets was found to be within
the specified limits (90% to 110%). This indicates that all the formulations of
diclofenac were passing the drug content uniformity. The values are given in
Table 10.
Table 10: Drug content of tablets.
Formulation * Absorbance Concentration (µg/ml) % Drug content
F1 0.1659+0.0030 5.115 102.3
F2 0.1673+0.0007 5.158 103.16
F3 0.3348+0.0003 10.271 102.71
F4 0.3353+0.007 10.286 102.86
F5 0.3387+0.0008 10.390 103.90
F6 0.3386+0.0006 10.387 103.87
* Each value is an average of 3 determinations
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 39
5.6.7 In-vitro dissolution study: -
The in-vitro dissolution of all the 6 formulations was carried out using USP
dissolution test apparatus and the results are given in following Tables.
Table 11: Dissolution data of F1. (Conventional tablets of diclofenac sodium)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.0000 0.000 0.000 0.000 15 0.2869+0.0014 8.809 39.641 79.282 30 0.3079+0.0015 9.45 42.525 85.050 45 0.3440+0.0071 10.552 47.484 94.968 60 0.3576+0.0052 10.968 49.356 98.712
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Table 12: Dissolution data of F2. (Conventional tablets of diclofenac calcium)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.0000 0.000 0.000 0.000 15 0.0454+0.0059 1.437 6.467 12.934 30 0.0577+0.0063 1.813 8.159 16.317 45 0.0743+0.0030 2.319 10.437 20.874 60 0.0963+0.0026 2.991 13.459 26.919 90 0.1148+0.0022 3.556 16.001 32.002 120 0.1347+0.0066 4.194 18.872 37.743 150 0.1581+0.0068 4.878 21.951 43.902 180 0.1829+0.0036 5.635 25.358 50.716 210 0.2126+0.0008 6.541 29.435 58.87 240 0.2495+0.0027 7.668 34.506 69.012 270 0.2950+0.0021 9.057 40.755 81.510 300 0.3465+0.0040 10.324 46.456 92.912 330 0.3625+0.0012 11.17 50.028 100.055
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 40
0
10
20
30
40
50
60
70
80
90
100
0 15 30 45 60 90 120 150 180 210 240 270 300 330
Time (min)
Per
cen
tag
e o
f D
rug
Rel
ease
F1
F2
Fig. 7: Comparative dissolution profile of formulations F1 and F2.
Conventional tablet of diclofenac sodium and diclofenac calcium.
The % amount of drug release v/s time (min) was plotted and depicted as
shown in Fig. 7.
Tablets containing diclofenac calcium showed decreased release rate for up to
6 hours compared to diclofenac sodium, which released in one hour. This reduction
in release may be attributed to the poor solubility of calcium salts. Hence calcium
salts of the drug can be exploited for the sustained release dosage forms.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 41
Table 13: Dissolution data of F3. (Diclofenac sodium matrix tablet 1:1)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.0000 0.000 0.000 0.000
15 0.0415+0.0056 1.318 5.931 5.931
30 0.0458+0.0061 1.449 6.522 6.522
45 0.0498+0.0041 1.571 7.072 7.072
60 0.0584+0.0054 1.834 8.253 8.253
75 0.0632+0.0034 1.981 8.915 8.915
90 0.0805+0.0075 2.509 11.291 11.291
105 0.0990+0.0039 3.073 13.829 13.829
120 0.1353+0.0045 4.182 18.817 18.817
150 0.2383+0.0049 7.326 32.966 32.966
180 0.3378+0.0029 10.368 46.659 46.659
210 0.4464+0.0012 13.68 61.564 61.564
240 0.4991+0.0032 15.29 68.809 68.809
270 0.5526+0.0019 16.922 76.15 76.15
300 0.5875+0.0023 17.987 80.942 80.942
330 0.6328+0.0014 19.369 87.159 87.159
360 0.6734+0.0020 20.608 92.736 92.736
390 0.7241+0.0034 22.156 99.701 99.701
420 0.7295+0.0046 22.321 100.443 100.443
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 42
Table 14: Dissolution data of F4. (Diclofenac sodium matrix tablets 1:2)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.0163+0.0024 0.549 2.471 2.471
30 0.0224+0.0012 0.735 3.308 3.308
45 0.0315+0.0016 1.013 4.558 4.558
60 0.0500+0.0019 1.577 7.096 7.096
75 0.0597+0.0020 1.876 8.445 8.445
90 0.0707+0.0012 2.212 9.957 9.957
105 0.0836+0.0021 2.604 11.72 11.72
120 0.1463+0.0060 4.519 20.337 20.337
150 0.1984+0.0052 6.110 27.497 27.497
180 0.2597+0.0093 7.982 35.921 35.921
210 0.3058+0.0016 9.388 42.248 42.248
240 0.3493+0.0083 10.715 48.218 48.218
270 0.4032+0.0060 12.360 55.623 55.623
300 0.4585+0.0049 14.048 63.219 63.219
330 0.5450+0.0061 16.691 75.112 75.112
360 0.5918+0.0097 18.118 81.533 81.533
390 0.6270+0.0138 19.191 86.359 86.359
420 0.6579+0.0106 20.136 90.616 90.616
450 0.6845+0.0022 20.948 94.267 94.267
480 0.7109+0.0035 21.753 97.889 97.889
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 43
Table 15: Dissolution data of F5. (Diclofenac calcium matrix tablets 1:1)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.0000
15 0.0511+0.0012 1.611 7.25 7.25
30 0.1102+0.0034 3.415 15.369 15.369
45 0.2412+0.0032 7.414 33.364 33.364
60 0.3361+0.0072 10.311 46.401 46.401
75 0.4262+0.0016 13.063 58.787 58.787
90 0.4892+0.003 14.987 67.444 67.444
105 0.5373+0.0021 16.455 74.051 74.051
120 0.5878+0.0025 17.998 80.994 80.994
135 0.6254+0.0047 19.143 86.143 86.143
150 0.6394+0.0067 19.570 88.065 88.065
165 0.6667+0.0066 20.405 91.824 91.824
180 0.6844+0.0050 20.945 94.256 94.256
195 0.7055+0.0038 21.589 97.154 97.154
210 0.7210+0.0022 22.061 99.275 99.275
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 44
Table 16: Dissolution data of F6. (Diclofenac calcium matrix tablets 1:2)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.0312+0.0025 1.004 4.516 4.516
30 0.0998+0.0021 3.098 13.94 13.94
45 0.1404+0.0035 4.337 19.517 19.517
60 0.2183+0.0036 6.715 30.221 30.221
75 0.2841+0.0043 8.725 39.263 39.263
90 0.3489+0.0031 10.704 48.171 48.171
105 0.4334+0.0012 13.283 59.775 59.775
120 0.5021+0.0022 15.379 69.205 69.205
135 0.5782+0.0049 17.702 79.65 79.65
150 0.6174+0.0041 18.899 85.049 85.049
165 0.6469+0.0050 19.799 89.099 89.099
180 0.6708+0.0088 20.529 92.382 92.382
195 0.6846+0.0018 20.950 94.278 94.278
210 0.7001+0.0071 21.423 96.404 96.404
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120 150 180 210 240 270 300 330 360 390 420
Time (min)
Per
cen
tag
e o
f D
rug
Rel
ease
F3
F5
Fig. 8:Comparative dissolution profile of formulations F3 and F5
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 45
0
20
40
60
80
100
120
0 30 60 90 120 180 240 300 360 420 480
Time (min)
Per
cent
age
of D
rug
Rel
ease
F 4
F6
Fig. 9: Comparative dissolution profile of formulations F4 and F6
Comparison of Diclofenac sodium release with Diclofenac calcium from matrix
tablets (Fig. 8 and 9).
As mentioned before, the release of diclofenac sodium from the conventional
tablet is better due to the solubility reason. It is a better soluble salt compared to other
salt forms. However, the release from the matrix tablets reduced drastically. There
may be complex mechanism involved in contrary to simple swelling, diffusion and
erosion concept. There was initial very slow release of drug for the first few minutes
approximately 105 minutes. This may be due to the inability of the tablet to reswell
quickly. However, once the tablet swelling was complete there was better release of
drug (after 120 minutes), resembles more or less similar to that of diclofenac calcium
from matrix tablet.
The initial delay in release from F3 may be due to the complex formation
between drug and polymer. Calcium is a divalent ion. Hence, there may be formation
of complex between diclofenac, calcium ions and alginate. This leads to very slow
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 46
release of the drug initially. However, when the complex breaks, the release rate may
suddenly increase for few minutes, followed by further reduction due to solubility of
diclofenac calcium, which is also present in the matrix.
F3 formulation released 100% of drug in 7hours, compared to F5 formulation,
which in turn released 99% of drug in just 4 hours. Based on solubility parameter and
in comparison to the conventional tablet dissolution profile, F5 was supposed to be
released in much slower rate compared to F3. But it released at a faster rate from the
matrix. Theoretically speaking, the release of drug from alginate matrix takes place
due to the combination of swelling, erosion and diffusion. However, this mechanism
is applicable as long as there is no interaction between drug and alginate. All the
formulations may have followed this mechanism except the formulation F3 as well as
F4. There may be some interaction between the drug and other ingredients responsible
for the formation of matrix by gelation method, as mentioned before.
The proposed mechanism for the delayed release of diclofenac sodium from
the matrix tablets is as follows:
Diclofenac sodium salt when dispersed in sodium alginate solution, some
amount may go into the solution. When calcium chloride is added to the dispersion to
form gelation, the dissolved part of the diclofenac sodium may get converted to the
diclofenac calcium along with the simultaneous formation of calcium alginate. IR
spectral studies revealed that there is a mixture of both the salts of diclofenac are
present in the diclofenac sodium matrix as peaks for both diclofenac sodium and
diclofenac calcium are present (as shown in fig. 15-19) It was observed that, there is a
significant difference in the physical appearance, between matrix formation of
diclofenac calcium in sodium alginate and diclofenac sodium in sodium alginate.
When calcium chloride solution was added to the sodium alginate solution containing
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 47
diclofenac sodium, a very white colored matrix was formed and this is may be due to
the milky precipitation of diclofenac calcium, with simultaneous formation of calcium
alginate. However, this physical appearance was not observed when calcium
diclofenac dispersed in sodium alginate. This suggests that, when calcium chloride
added to the sodium alginate solution containing sodium salt of drug and caused
gelation, may lead to some sort of complexation between drug and polymer, which in
turn may releases, the drug slowly. The complexation formation can be ruled out
when calcium salts are placed in alginate and no gelation occurs. This indicates that
the calcium ion is having greater affinity to the drug than alginate.
This mechanism may not exist in the formulation F5, where simple swelling,
diffusion, erosion or disintegration with dissolution mechanism may exist. As a result,
drug releases at a faster rate.
Hence, the release of sodium salts of the drug from alginate can be expected more
slower than calcium salts, though calcium salts are less soluble.
0
20
40
60
80
100
120
0 15 30 45 60 90 120 150 180 210 240 270 300 330
Time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F2F5
Fig. 10: Comparative dissolution profile of formulations F2 and F5
.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 48
Comparison of diclofenac calcium release from the conventional and matrix
tablets (Fig. 10)
In contrast to the nature of drug release of diclofenac sodium from both
conventional and matrix tablets, diclofenac calcium was released better from matrix
tablets (Table 12 and 15). The release rate of diclofenac calcium from matrix was
initially slow (for 15 minutes) followed by rapid release for next one hour. However,
the release of diclofenac calcium from conventional tablet was better initially (for 15
minutes) compared to the matrix tablet, followed by very slow release of the drug.
In 330 minutes, 100% of drug was released from conventional tablet, where
as matrix tablets released the same amount in 210 minutes.
The initial slow release of the drug from the matrix tablet is attributed to the
reswelling property of alginate and diffusion of the drug. However, the sudden
increment in release after 15 minutes is due to the reason that the tablet disintegrates
faster and the release is attributed to the solubility of the drug. The reswelling nature
of alginate helps in disintegration. However, the conventional tablet disintegrated at a
much slower rate. As a result, the release was delayed until complete disintegration of
the tablet. Once the tablet disintegrated the release profile observed remained more or
less similar to that obtained with conventional tablets. Hence, calcium diclofenac salts
can be used for controlled release formulations.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 49
Table 17: Dissolution data of Voveran-50 (conventional tablet)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.1742+0.0024 5.369 24.161 48.322
30 0.2890+0.0052 8.874 39.931 79.862
45 0.3225+0.0042 9.896 44.533 89.066
60 0.3654+0.0069 11.206 50.426 100.852
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Table 18: Dissolution data of Nac-50 (conventional tablet)
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.2968+0.0054 9.112 41.004 82.008
30 0.3315+0.0057 10.171 45.769 91.538
45 0.3485+0.0072 10.69 48.104 96.209
60 0.3589+0.0089 11.007 49.533 99.006
* Each value is an average of 3 determinations.
D.F= Dilution Factor, SD= Standard Deviation
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 50
Table 19: Dissolution data of Voveran SR-100.
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.1168+0.0009 3.617 16.275 16.275
30 0.1392+0.0015 4.301 19.355 19.355
60 0.1974+0.0025 6.077 27.348 27.348
90 0.2014+0.0022 6.199 27.897 27.897
120 0.2341+0.0031 7.198 32.389 32.389
150 0.2846+0.0051 8.739 39.326 39.326
180 0.3351+0.0041 10.281 46.264 46.264
210 0.4083+0.0032 12.515 56.319 56.319
240 0.4469+0.0029 13.694 61.622 61.622
270 0.4734+0.0025 14.503 65.262 65.262
300 0.5058+0.0015 15.492 69.713 69.713
330 0.5306+0.0008 16.249 73.12 73.120
360 0.5568+0.0016 17.049 76.719 76.719
390 0.5892+0.0012 18.038 81.17 81.170
420 0.6198+0.0022 18.972 85.373 85.373
450 0.6428+0.0021 19.674 88.533 88.533
480 0.6799+0.0016 21.267 95.703 95.703
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 51
Table 20: Dissolution data of Divon SR-100
Time (min)
*Absorbance (nm)
Conc. (µg/ml)
‘C’
Amount of drug released
(mg) (Cx900xD.F/1000)
% Drug released
0 0.000 0.000 0.000 0.000
15 0.0981+0.0020 3.046 13.707 13.707
30 0.1240+0.0025 3.837 17.264 17.264
60 0.1392+0.0022 4.301 19.353 19.353
90 0.1798+0.0024 5.540 24.93 24.930
120 0.2019+0.0041 6.215 27.966 27.966
150 0.2400+0.0052 7.378 33.2 33.200
180 0.2890+0.0031 8.874 39.931 39.931
210 0.3250+0.0062 9.972 44.876 44.876
240 0.3810+0.0019 11.682 52.569 52.569
270 0.4416+0.0015 13.532 60.894 60.894
300 0.4718+0.0009 14.454 65.042 65.042
330 0.5069+0.0072 14.525 69.864 69.864
360 0.5375+0.0059 16.459 74.068 74.068
390 0.5689+0.0045 17.418 78.381 78.381
420 0.6092+0.0037 18.648 83.917 83.917
450 0.6348+0.0032 19.430 87.434 87.434
480 0.6768+0.0023 20.712 93.203 93.203
* Each value is an average of 3 determinations.
D.F= Dilution Factor (5)
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 52
0
20
40
60
80
100
120
0 30 60 90 120 150 180
Time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F1F2
Voveran-50Nac-50
Fig. 11: Comparative Dissolution profile of Marketed conventional tablets and
formulations F1 and F2
0
20
40
60
80
100
120
0 30 90 150 210 270 330 390 450
Time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F4F2Voveran SR - 100Divon SR - 100
Fig. 12: Comparative Dissolution profile of Marketed sustained release tablets
and formulations F2and F4
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 53
Comparison with Marketed products.
The evaluation parameters tested and compared was in-vitro dissolution
profile. The values obtained for in-vitro dissolution data are given in Table17 to 20
and the dissolution profiles are given in Fig. 11 and 12.
The conventional marketed tablets of diclofenac sodium gave 100% drug
release in 1 hour of dissolution study. Formulation F1 showed similar release profile
compared to marketed tablet, F2 showed slower release rate compared to marketed
formulation, indicating calcium salts are suitable for sustaining the drug release.
The sustained release marketed tablets such as Voveran-SR-100 gave 95% of
drug release in 8 hour while Divon-SR-100 gave 93% of drug release in 8 hours of
dissolution study. Formulation F4 showed similar release profile as marketed tablets
i.e. 98% of drug release in 8 hours of dissolution study.
Comparison of ratios:
As the concentration of polymer increases, the release rate was found to be
decreased as shown in figure 13 and 14. In general more amount of polymer reduces
the entrapment efficiency and also the diffusion length may increase. This may result
in delayed release of the drug.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 54
0
20
40
60
80
100
120
0 30 60 90 120 180 240 300 360 420 480
Time (min)
Per
cen
tag
e o
f D
rug
Rel
ease
F3
F4
Fig. 13: Comparative dissolution profile of Formulations F3 and F4.
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120 135 150 165 180 195 210
Time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F5
F6
Fig. 14: Comparative dissolution profile of Formulations F5 and F6.
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 55
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 56
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 57
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 58
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 59
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 60
5.7 Curve Fitting Analysis:
The release data of diclofenac were fitted to models representing zero order
and first order kinetics. The data were processed for regression analysis using MS
EXCEL statistical function. The corresponding regression co-efficient values are
shown in Table 21.
Table 21: Comparison of Regression co-efficient values for different
formulations.
Regression co-efficient values
“R2 values” Formulation
Zero Order First order
F3 0.9707 0.9010
F4 0.9906 0.8686
F5 0.9041 0.7028
F6 0.9662 0.7974
The pattern of drug release (Fig: and) and the regression co-efficient values
(Table 20), both indicate the zero order release kinetics from the matrix tablets. (R2
value was above 0.95 for all the formulation on an average).
Release of drug from matrix tablets containing hydrophilic polymers involves
factors of diffusion. As a gradient varies, the drug is released, and the distance for the
diffusion increases, which is referred as Higuchi’s kinetics. The in-vitro release
profiles of drug from all the formulations could be best expressed by Higuchi’s
equation and regression co-efficient values were found out and given in table 22.
Table 22: Regression co-efficient values of different formulations for the Higuchi
plot.
Formulation Co-efficient of Correlation values “R2 values”
F3 0.9365 F4 0.9538 F5 0.9702 F6 0.9798
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 61
The Higuchi plot, square root of time and % amount drug release for all the
formulations are shown in Fig. 20 – 23.
The figures indicate a linear relationship throughout the study as the R2 values
range from 0.9365 to 0.9798. The appearance of straight line indicated that the release
was diffusion rate limited. Initial variation in linearity for F3 and F4 (Fig 20 and 21)
is due to the complex mechanism involved for the sodium salt of drug in matrix.
However the same mechanism can be for F5 and F6 (Fig 22 and 23).
0
20
40
60
80
100
120
0 5 10 15 20 25
Square root of time (min)
Per
cen
tag
e o
f D
rug
Rel
ease
F3
Fig. 20: Higuchi plot of formulation F3
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 62
0
20
40
60
80
100
120
0 5 10 15 20 25
Square root of time (min)
Per
cen
tag
e o
f D
rug
Rel
ease
F4
Fig. 21: Higuchi plot of formulation F4
0
20
40
60
80
100
120
0 5 10 15 20
Square root of time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F5
Fig. 22: Higuchi plot of formulation F5
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 63
0
20
40
60
80
100
120
0 5 10 15 20
Square root of time (min)
Per
cen
tag
e o
f Dru
g R
elea
se
F6
Fig. 23: Higuchi plot of formulation F6
5.8 Stability study:
The results of the stability study of the tablets at room temperature (27°C), at
45°C and at 60°C are shown in Table23 and 24.
Table 23: % Drug Content of formulations F3 and F4 under different conditions.
Percentage Drug Content
F3 F4 Time in weeks
* RT 45°C 60°C * RT 45°C 60°C
0 102.95 102.97 102.89 102.86 103.41 103.04
2 102.89 102.92 102.86 102.84 103.40 103.06
4 102.80 102.85 102.79 102.99 103.35 102.98
6 102.72 102.73 102.72 102.73 103.32 102.94
8 102.69 102.68 102.61 102.63 103.52 103.15
* RT Room Temperature
Ch. 5Result and Discussion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 64
Table 24: % Drug Content of formulations F5 and F6 under different conditions.
Percentage Drug Content
F5 F6 Time in weeks
* RT 45°C 60°C * RT 45°C 60°C
0 103. 80 104.12 103.65 104.45 104.12 103.87
2 103.82 104.14 103.62 104.42 104.16 103.80
4 103.75 104.16 103.67 104.32 103.89 103.72
6 103.65 103.95 103.61 104.40 103.91 103.76
8 103.66 103.97 103.45 104.38 103.85 103.69
* RT Room Temperature
The results of stability studies indicate that all the formulations are found to be
stable when stored under different conditions.
C.h. 5 R
esults and Discussion
Dept of P
harmaceutics, N
.G.S.M
.I.P.S, M
angalore 55
Fig 15: IR Spectra of Sodiumalginate
C.h. 5 R
esults and Discussion
Dept of P
harmaceutics, N
.G.S.M
.I.P.S, M
angalore 56
Fig 16: IR spectra of Diclofenac sodium
C.h. 5 R
esults and Discussion
Dept of P
harmaceutics, N
.G.S.M
.I.P.S, M
angalore 57
Fig 17: IR spectra of Diclofenac sodium matrix
C.h. 5 R
esults and Discussion
Dept of P
harmaceutics, N
.G.S.M
.I.P.S, M
angalore 58
Fig 18: IR spectra of Diclofenac calcium
C.h. 5 R
esults and Discussion
Dept of P
harmaceutics, N
.G.S.M
.I.P.S, M
angalore 59
Fig 19:IR spectra of the Diclofenac calcium matrix
Ch. 6 Summary
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 65
SUMMARY The goal in the development of controlled drug delivery systems is to develop
systems that are safe, reproducible and effective. Matrix tablets are controlled release
matrix drug delivery systems containing drug through out the structure and governs
the release rate of the entrapped active substance.
Diclofenac is an non-steroidal anti- inflammatory drug (NSAID), used for
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute musculoskeletal
injury and dysmenorrhea. Due to its short half- life, the frequency of administration is
more and importantly it produces frequent side effects are gastrointestinal
disturbances, peptic ulceration and gastrointestinal bleeding. Hence in this study an
attempt has been made to formulate a calcium salt of diclofenac and formulate into
conventional and matrix tablets and compare its release with the diclofenac sodium
salt conventional tablets and matrix tablets.
Calcium salts of diclofenac was prepared by adding a 7.5mmoles of calcium
chloride solution drop by drop till precipitation is complete into 1% diclofenac
sodium solution and the precipitate formed was washed and dried.
Alginate matrix tablets of diclofenac sodium and diclofenac calcium were
prepared by ionic gelation method. The ionic gelation process involves the stacking of
glucuronic acid blocks of alginate chains with the formation of egg box junction,
which acts as a barrier for drug release. The matrices of diclofenac sodium and
diclofenac calcium were prepared in 1:1 and 1:2 drug: polymer ratios.
The percentage yield of matrix was found to be in the range of 78.5% to
89.5%. The yield was found to be the highest in the case of lowest drug to polymer
ratio. The drug content in the calcium alginate matrix was found to be highest in case
of diclofenac cal matrix than compared to diclofenac sodium matrix. This may be
Ch. 6 Summary
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 66
probably due to the more solubility of diclofenac sodium compared to diclofenac
calcium, that may be lost during the washing stage.
UV scanning of the prepared matrix containing the drug shows the peak at
276nm, which confirms the presence of diclofenac in matrix.
The tablets were prepared by direct compression. The drug release from the
diclofenac calcium conventional tablets was found to be slowest compared to
diclofenac sodium conventional tablets. This may be attributed to the less solubility of
calcium salts compared to sodium salts.
The drug release from the matrix tablets was found to be zero order, with the
slowest release up to 8 hours obtained from diclofenac sodium matrix tablets with the
drug to polymer ratio of 1:2. The drug release from diclofenac calcium matrix tablets
was found to be higher compared to diclofenac sodium matrix tablets.
When calcium chloride solution was added to the sodium alginate solution
containing diclofenac sodium, a very white colored matrix was formed and this may
be due to the milky precipitation of diclofenac calcium from diclofenac sodium, with
simultaneous formation of calcium alginate. However, this physical appearance was
not observed when diclofenac calcium dispersed in sodium alginate. This may lead to
some sort of complexation between drug and polymer, which in turn may releases,
drug slowly. IR spectral studies revealed the presence of diclofenac sodium and
diclofenac calcium in the matrix of diclofenac sodium matrix. Therefore the drug
release from the diclofenac sodium is reduced drastically.
The Higuchi plot was linear for majority of the drug release, indicating the
release was diffusion rate limited. Initial variation in linearity is due to the complex
formation in formulations F3 and F4. Hence, the drug release is diffusion rate limited.
Stability study indicated that all the formulations were found to be stable when
stored at different temperatures.
Ch. 7 Conclusion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 67
CONCLUSION
The following conclusions are drawn from the results and discussion described in
previous chapter.
Ø Diclofenac calcium salt was prepared by precipitation method and formation
of calcium salt of drug was confirmed by calcium oxalate and flame test.
Ø Conventional tablets were prepared by direct compression method. The
prepared tablets showed relatively good hardness and drug content was within
pharmacopoeial limits. In vitro release study show slow release for diclofenac
calcium compared to diclofenac sodium, since calcium salts are less soluble
than sodium salts.
Ø Matrix of drugs were prepared by ionic gelation method and based on the
amount of drug loaded in matrix, the entrapment efficiency was calculated.
Entrapment efficiency of diclofenac calcium was greater than diclofenac
sodium, since the solubility of diclofenac sodium is more; it got loss more and
lost during washing stage.
Ø Matrix tablets were prepared by direct compression, showed good hardness
and friability. In-vitro release showed slow release of drug in case of
diclofenac sodium in matrix compared to diclofenac calcium in matrix. IR
spectral study revealed the presence of both salts in diclofenac sodium matrix.
This may be reason for the slow release of the drug. Initial difference in
release is due to swelling takes place immediately in case of diclofenac
calcium matrix compared to sodium matrix
Ø The release of drug from matrix tablets takes place by swelling, diffusion and
erosion mechanism along with the some complex mechanism in diclofenac
sodium matrix.
Ch. 7 Conclusion
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 68
Ø The order of drug release was found to be zero order for all the matrix tablets.
Drug release data was better suitable to Higuchi’s diffusion model and the
release of drug was diffusion rate limited from all the matrix tablets.
From, the above findings, it is concluded that calcium diclofenac can be used
for sustained release formulation, provided if further in-vivo studies should be carried
out. Further the release of diclofenac sodium from alginate matrix indicated that, an
ideal approach for sustained release dosage form. Alginate not only avoids the drug
release in stomach, also proved as a mucoprotective agent. Hence it avoids the
irritation to the mucus layer of intestine. The complex formation and subsequent slow
release of sodium salt of drug is an advantage of using alginate as an matrix forming
material.
Ch. 8 Bibliography
Department of Pharmaceutics, N.G.S.M.I.P.S, Mangalore. 69
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