Int J Pharm Sci Tech (© 2009)

Vol. 2, Issue-1, JAN-JUNE, 2009

ISSN: 0975-0525 RESEARCH ARTICLE
PHARMACEUTICAL CHARACTERIZATION AND ASSESSMENT OF DRUG RELEASE BEHAVIOUR OF
DICLOFENAC SODIUM EXTENDED RELEASE MATRIX DEVICES
Nikhil K Sachan, and Seema Pushkar*
University Institute of Pharmacy, C.S.J.M. University, Kanpur – 208 024, U.P. (India)
Received:20.02.09; accepted:17.05.09 ; published:30.06.09
ABSTRACT:
The objective of this study was to develop the extended release tableted matrix devices for once daily dosing of
diclofenac sodium, and their evaluation for performance and compliance with official pharmacopoeial and allied pharma-
ceutical requirements. The matrix tablets were prepared by drug incorporated polymer matrix, formulated using different
combinations and ratios of hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (Sodium CMC), and
sodium alginate (NaAlg). Several preformulation trials were conducted to study the effect and optimization of various
formulation and process parameters. The drug loaded polymeric matrices so prepared were compressed to tablets and
studied for drug the release behaviour and comparative kinetic characterization along with six popular marketed brands of
Diclofenac – SR tablets. Dissolution testing for modeling of drug release kinetics was conducted as per the SUPAC
guidelines provided by FDA for modified release dosage forms. The formulated granules and tablets compressed com-
plied with compendial and mechanistic requirements. The in vitro results shown a better release profile of formulated
delivery system when compared to marketed brands extended up to 24 hours. The various formulations have shown an
extended release up to 11 – 23 hours in different release environments.

Key words: Pharmaceutical characterization, SR tablets, diclofenac sodium, drug release.

INTRODUCTION: cacy and safety of drugs, administered by conventional meth-

During recent years, considerable attention has been focused
on the development of new drug delivery systems for a num-
ber of reasons as (1) the recognition of possibility of re-
patenting successful drugs by applying the concepts and tech-
niques of controlled release drug delivery system, coupled
with the increasing expanse in bringing new drug entities to
the market, has encouraged the development of new drug
delivery systems. (2) new systems are needed to deliver the
novel, genetically engineered pharmaceuticals, for example,
peptides and proteins to their sites of action without incur-
ring significant immunogenicity or biological inactivation (3)
treating enzyme deficient diseases and cancer therapies can
be improved by better targeting1. Finally therapeutic effi-
Address for Correspondence:
*Seema Pushkar
University Institute of Pharmacy,
C.S.J.M. University, Kanpur – 208 024
Uttar Pradesh (India)
E-mail: seemapushkar@gmail.com
ods, can be improved by more precise spatial and temporal
placement within the body, thereby reducing both the size
and number of doses2. The goal of developing the new drug
delivery systems is to provide drug release in an amount suf-
ficient to maintain the therapeutic drug level over extended
period of time, through the predominantly controlled release
profiles by special technological construction and design of
the system itself 3. The pharmaceutical industry provides a
variety of dosage forms and dosage level of particular drugs,
thus enabling the physician to control the onset and duration
of drug therapy by altering the dose and /or mode of admin-
istration. In some instances, control the drug therapy can be
achieved by taking advantages of beneficial drug interaction
that affect drug disposition and elimination4. Mixture of drugs
might be utilized to potentiate, synergize, or antagonize given
drug actions. Alternatively drug mixtures might be formulated
in which the rate and /or extent of drug absorption is modi-
fied. Sustained release dosage forms design embodies this
approach to control the drug action that means through a
process of either drug modification or dosage form modifi-

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Vol. 2, Issue-1, JAN-JUNE, 2009
 Int J Pharm Sci Tech (© 2009)
cation, the absorption process and subsequently drug action, quantities of hydroxy propyl methyl cellulose, sodium algi-
can be controlled5. nate and sodium carboxy methylcellulose along with drug
One of the first commercially available product to provide sus- for F1 to F6 (Table 1) mixed by geometric dilution method
tained release of a drug formulation was Dexedrine spansules®, in a double cone mixer at 90 rpm for 15 min. The granu-
made by Smith Kline & French6. After this many more sus- lating agents (water for F1 to F5, and 4 % ethanolic solu-
tained release products came to the market, some successful, tion of ethyl cellulose for F6) were added slowly to this
others potentially lethal. Each delivery system was aimed at elimi- blend. After enough cohesiveness was obtained the mass
nating the cyclical changes in plasma concentration seen after was sieved through 22 mesh size and the granules so ob-
the administration of conventional delivery system7. tained were dried in an oven at 40° C and were kept in a
With most orally administered drugs, targeting is not a desiccators for 12 hr. talc and magnesium stearate were
primary concern, unless for the drugs having very specific ab- finally added as glidant and lubricant, the tablets were com-
sorption window, as it is usually intended for drugs to permeate pressed using a single punch tablet machine9.
to the general circulation and perfuse to other body tissue rather
it is desired to get a controlled absorption providing prolonged
duration of action and minimizing the side effects. For this rea-
son, most systems employed are of the sustained release vari-
ety. It is assumed that increasing concentration at the absorption
site will increase the rate of absorption and therefore increase
circulating blood level which in turn promotes greater concen-
tration of drug at site of action. If toxicity is not an issue, thera-
peutic level can thus be extended. In essence, drug delivery by
these systems usually depends on release from some type of
dosage form, permeation though the biological milieu, and ab-
sorption though epithelial membrane to the blood8.
The present study focus on the release retardant matrix tablet
dosage form for controlled release of diclofenac sodium using
polymer backbone of HPMC, sodium alginate and sodium
carboxy methylcellulose in different combinations and ratios. The
diclofenac sodium is well established anti-inflammatory drug. The
aim of study is to develop a once daily sustained release tablet
dosage form of diclofenac sodium by optimizing the release profile The prepared tablets were studied for thickness,
of drug through varying the composition of polymer backbone. diameter, diameter/height ratio (D/H ratio), hardness,
2. MATERIALS AND METHODS: weight variation, drug content, and in vitro drug release
2.1. Materials: studies; before tablet preparation, the granules were evalu-
Diclofenac sodium was kindly gifted by the Apco Pharmaceuti- ated for angle of repose, bulk density, hausner’s ratio, com-
cals Ltd. (Haridwar), Cetosteryl alcohol (CDH, New Delhi), pressibility index and particle size determination.
Magnesium stearate (SD fine chemicals New Delhi), Sodium
hydroxide (Ranbaxy fine chemicals), Spray dried lactose (Merk 2.2.2. Estimation of Drug:
India Ltd., Mumbai), Sodium hydrogen phosphate (Merk India The content of diclofenac sodium in tablets and its release
Ltd. Mumbai) and Disodium hydrogen phosphate (Merk India as a function of time was estimated spectrophotometri-
Ltd. Mumbai). The marketed brands of the Diclofenac Sodium cally using an UV spectrophotometer (U2001 Hitachi, Ja-
SR tablets taken in present study were Nac SR, Voveran SR, pan) based on the measurement of absorbance at 276 nm
Relaxyl SR, Zobid SR, Vovo SR and Divon SR. (l max) in aqueous buffer medium (pH 6.8) using standard
2.2. Methods: plot10, 11.
2.2.1. Preparation of Matrix Tablets:
The matrix tablets were prepared by mixing the corresponding 2.2.3. Evaluation of Granules:
2.2.3.1. Angle of repose: The angle of repose of gran-

Vol. 2, Issue-1, JAN-JUNE, 2009 -15-


ules was determined by the funnel method. Weighed quantity
of granules were taken in and poured from funnel and height of
the funnel was adjusted in such a way that the tip of the funnel
just touched the apex of the heap of the granules. The diameter
of the powder cone was measured and angle of repose was
calculated12 using formula tan è = h/r.
2.2.3.2. Bulk density: Both loose bulk density (LBD) and
tapped bulk density (TBD) were determined. A quantity of 20
gm of powder from each formula, previously lightly shaken to
break any agglomerates formed, was introduced into a 50 ml
measuring cylinder. After the initial volume was observed, the
cylinder allowed falling under its own weight onto a hard sur-
face from the height of 0.5-1.5 cm at 5 sec intervals. The tap-
ping has continued until no further change in volume was noted.
LBD and TBD were calculating using these formulas13.
LBD = weight of the powder/ volume of packing
2.2.3.3. Compressibility: The compressibility and flow prop-
erty of the granules was determined by Carr’s compressibility
index and Hauser’s ratio calculated as below14:
Carr’s compressibility index (%) =
[(TBD-LBD) ×100/TBD] ------ (1)
Hausner’s ratio = [TBD/LBD × 100] ---- (2)
2.2.3.4. Particle size determination: A sieve stack with six
sieves in aperture progression was loaded with powder on to
the coarsest sieve of the assembled stack and nest is subjected
to mechanical vibration. After 10 min, the particles are consid-
ered to be retained on the sieve mesh; then weighed the pow-
der retained in the sieves and the respective parameters were
calculated15
2.2.4. Evaluation of Tablets:
2.2.4.1. Dimensional Analysis: The thickness and diameter
of tablets was determined using vernier caliper. Twenty tablets
from each batch were used and average values were calcu-
lated.
2.2.4.2. Hardness: For each formulation, the hardness of six
tablets was determined using the Monsanto hardness tester and
average value were calculated9, 16.
2.2.4.3. Weight variation test: Twenty tablets were selected
at random from each of the batch. Average weight and maxi-
mum percent deviation (positive and negative) were determined9,
17
. tained, similarity testing was also performed using pair
2.2.4.4. Content uniformity: Twenty tablets were weighed
and powdered accurately, a quantity of powder equivalent to
50 mg of diclofenac sodium, shaken with 60 ml of methanol in
a 200 ml volumetric flask and dilute to volume with methanol.
Dilute 5 ml of this solution with 100 ml of methanol and mea-
Vol. 2, Issue-1, JAN-JUNE, 2009
Int J Pharm Sci Tech (© 2009)
sure the absorbance of resulting solution at the maximum
max
284.5 nm. Calculated the content of
C14H10Cl2NNaO2 from the absorbance obtained by re-
peating the procedure using diclofenac sodium. Declared
the content of C14H10Cl2NNaO2 in diclofenac sodium9
2.2.4.5. In-vitro drug release study: The release of
diclofenac sodium from the tablets was studied in buff-
ered aqueous medium as per USP guidelines using USP
XXVI Dissolution test apparatus basket type (Campbell
Electronics, Mumbai) at 37± 0.2 0 C with a rotating speed
of 75 rpm18, 19. At preset time intervals 5ml aliquots were
withdrawn and replaced by an equal volume of fresh dis-
solution medium. The samples were withdrawn through a
membrane filter (0.45 mm) and were analyzed for drug
content spectrophotometrically. The in vitro dissolution
profile studies for characterization of release kinetics were
carried as per the SUPAC guidelines for the modified re-
lease dosage forms20.
The concentration of diclofenac sodium was corrected
for sampling effects according to the following equation:
---- (3)
Where, Cn is the corrected concentration of the
nth sample, Mn is the measured concentration of the nth
sample, VT is the volume of the dissolution medium, VS
is the volume of the sample withdrawn, Cn-1 is the
corrected concentration of the (n-1)th sample, and
Mn-1 is the measured concentration of the (n-1)th
sample,
2.2.5. Statistical Analysis:
Data presented in the drug release figures are
“mean” of the triplicate study except when otherwise
stated. Statistical comparisons were made using Student’s
t-test (P< 0.05). The 95 % confidence interval was cal-
culated for the slope of the line when the fraction re-
leased was plotted as a function of time in different ki-
netic models. Results are given as means ± standard er-
rors of the mean (S.E.M.).
For comparison of multiple dissolution profiles ob-
wise dissolution data obtained in each individual medium
by calculating the similarity factor (F ) as per the SUPAC
guidelines for modified-release dosage forms. This fac-
tor is a logarithmic reciprocal of square root transforma-
tion of one plus the average mean squared (average sum
of squares) differences of drug percent dissolved between
the two dissolution profiles over all time points.
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---(4)
Where n is the number of dissolution time points and
RJ and TJ are the dissolution values of two dissolution
profiles at time t. The two dissolution profiles are consid-
ered similar when F value is in range of 50 to 100.
Mean dissolution time (MDT) was estimated from
the cumulative mass dissolved vs time profile by using the
following equation21, 22:
----- (5)
Int J Pharm Sci Tech (© 2009)
± 0.01 g/cc. Angle of repose (f) ranged from 16.29 ± 0.04
to 21.57 ± 0.04 that reflects good flow property. The re-
sults of Carr’s compressibility index and Hausner’s ratio
have also supported good flow behaviour of granulated for-
mulations (Table 2).
3.1. Evaluation of prepared tablet formulations:
3.1.1. Pharmaceutical Characterization:
All the formulations showed uniform thickness,
meter and D/H ratio. The thickness of tablets ranged from
7.2 ± 0.02 to 7.15 ± 0.05mm, diameter 10.04 ± 0.05 to
10.06 ± 04mm and D/H ratio of tableted granules was
1.4 ± 01 prepared formulation shown sufficient uniformity
in drug content(Table-3)

Where ‘i’ is the sample number, n is total number of

sample times, tmid is the sample the time at the mid point
between i and i-1, and ÄXd is additional mass of drug dis-
solved between i and i-1. Dissolution efficiency (DE) was
estimated form the cumulative % drug release vs time pro-
files by using this equation22, 23:

----- (6)

Release rate was estimated from the slope of amount

of drug release vs time plot
2.2.6. Modeling and Comparison of Release Pro-
files:
Data obtained from in vitro release studies were fit-
ted to various kinetic equations23 using the Microsoft Ex-
cel and SPSS software, to find out the mechanism of drug
release from matrix tablets. The kinetic models used were
Zero order (cumulative %drug release vs time), first order
(log cumulative %drug release vs time), Higuchi model (cu-
mulative %drug release vs log time), and Korsemeyer-
Peppas model (log cumulative %drug release vs log time).

3. RESULTS:
The different formulations of matrix granules were for-
mulated, and were evaluated for the particle size and allied
properties. Particle size of the prepared granules was found
in range of 82.97 ± 0.48 to 197.98 ± 0.54 mm and bulk
density measurements range from 0.256 ± 0.06 to 0.689

Vol. 2, Issue-1, JAN-JUNE, 2009 -17-


3.1.2. In vitro dissolution study:
The in vitro dissolution studies have been recognized as
an important element in the drug formulation development.
Under certain conditions it can be used as a surrogate for the
assessment of bioequivalence (Costa and Lobo, 2001)23. In
present study the in vitro dissolution testing was done to check
the compliance with compendial limit and to judge the sus-
tained release potential of prepared tablets (Fig.1), also the in
vitro dissolution testing was utilized as a tool for comparison
of the performance of prepared tablets with marketed brands.
Formulation F1 to F4 released about 80 to 90% of the drug
within only up to 12 hours. This may be due to the erosion of
sodium alginate cross-linking in alkaline medium those results
in faster exhaust of drug from the matrix after initial hours. The
sodium-CMC released drug at faster rate than did HPMC at
the same drug polymer ratio. The faster dissolution rates ob-
served in sodium-CMC could be due to its swellability and
disintegration property at intestinal conditions. Formulation F5
with drug to polymer ratio 1:4 using water as granulating agent
showed drug release for 24 hours, but with initial burst effect.
F6 formulated with EC 4% w/v ethanolic solution as granulat-
ing agent retarded the drug release up to 24 hours without
initial burst and followed zero order kinetics (r2= 0.9872).
The F6 was therefore selected as most successful formulation
for further comparison with marketed brands.
3.2. Modeling and characterization of drug release profiles:
3.2.1. Comparison of dissolution profiles:
The in vitro dissolution testing was performed in tripli-
cate to judge the reliability and scientific significance of the
data. Therefore the statistical comparison of such multiple dis-
solution profiles of the formulation becomes necessary for the
scientific reliability and is recommended for the regulatory
purpose. Classical statistical methods (e.g. standard devia-
tion, student’s t test, ANOVA etc) have long been used for the
comparison of multiple release profiles. Model independent
methods have recently drawn attention for statistical compari-
son of multipoint dissolution profiles and these include the dif-
ference factor and the similarity factor (Moore and Flanner,
1996)24. The similarity factor has been adopted by the Center
for Drug Evaluation and research (CDER- FDA)20 and by
Human Medicine Evaluation Unit of European Agency for the
Evaluation of Medicinal Products (EMEA)25, as a criterion
for the assessment of similarity between the multipoint in vitro
dissolution profiles and is included in the SUPAC-IR, SUPAC-
Vol. 2, Issue-1, JAN-JUNE, 2009
Int J Pharm Sci Tech (© 2009)
MR, and EMEA Guidelines (1999). The similarity factor
(F) as defined by FDA and EMEA is a logarithmic recipro-
cal square root transformation of one plus the mean square
(the average sum of squares) difference of drug percent
dissolved between the test and reference products. The two
dissolution profiles are considered significantly similar when
the “F” value is in the range of 50 to 100. This criterion, for
comparison of multipoint dissolution data, was adopted in
present study and multiple release profiles were compared
pair-wise using the said similarity factor for the scientific
significance and reliability. It was found that the dissolution
data obtained in triplicate study was reproducible with ac-
ceptable similarity.
3.2.2. Kinetic modeling of drug release profiles:
The quantitative interpretation of the values obtained
in the dissolution study is facilitated by the usage of generic
equations that mathematically translate the dissolution curve
in function of some parameters related with the pharma-
ceutical dosage forms (Costa and lobo, 2001)20. Mathemati-
cal modeling of controlled drug delivery can help to pro-
vide a scientific knowledge base concerning the mass trans-
port mechanisms that are involved in the control of drug
release. In an ideal case, the system formulation param-
eters required to achieve a certain desired drug release pro-
files can be predicted. Thus mathematical modeling can sig-
nificantly facilitate the optimization of existing and the de-
velopment of new pharmaceutical products26.
When developing new controlled release systems for
elucidating drug release mechanisms, the choice of appro-
priate mathematical model strongly depends on the type of
drug, type of excipients and composition of the device.
Various mechanisms can be used to control drug release;
diffusion, water triggered transport (swelling) and degrada-
tion / erosion are the most important ones. The in vitro re-
lease data was fitted to zero order, first order, Hinguchi
model and Korsymer-peppas model and the model with
highest correlation coefficient is then selected. From the lin-
ear portions of the curve slope and correlation coefficients
were calculated using MS excel and SPSS statistical soft-
ware. Relying over this finding the models explaining the
drug release behaviour and kinetics, the formulated matrix
tablets has shown zero order release kinetics with highest
correlation (Table 4).
3.3. Comparison of best formulation with marketed brands:
Formulation F6 that shown the best drug release pro-
file was selected as successful formulation and was com-
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 Int J Pharm Sci Tech (© 2009)

pared for pharmaceutical fitness and drug release perfor-

mance with the marketed brands of diclofenac-SR tablets
(Table 5). On the basis of evaluation criteria, the formula-
tion F6 has shown comparatively better and extended re-
lease with zero order kinetics and having adequate Phar-
maceutical acceptance. The several marketed brands were
evaluated and of that the best one was selected for com-
parison with the formulation F-6. The F-6 formulation has
shown at par with the standards and comparatively better
pharmaceutical parameters and drug release profile that
could be regarded as successful formulation.

4. DISCUSSION:
The UV-spectrophotometric scan has reported max of
diclofenac sodium in phosphate buffer pH 6.8, to be 276 nm
and in methanol 284 nm, which was in agreement to the
reported max of diclofenac sodium in respective solvents (USP
2004) and is used in estimation of drug during the study. The
Tabel
particle size, flow properties, compressibility and Hausner’s
ratio of all the granulation was satisfactory for tableting. The
compressed tablets with differently formulated granules have
been found to be varying although the tablet hardness is not an
absolute indicator of strength. The formulation F6 showed a
comparatively high hardness value of 7.5 ± 0.02 kg/cm2. This
could be due to presence of ethyl cellulose, which is generally
Table 5: Comparison between the best marketed brand responsible for more hardness of the tablet. The low hardness
(B2) and most optimum tablet formulation (F6) value was observed with formulation F1 may be due to pres-
ence of sodium CMC, which generally have disintegrating
property. So hardness of F6 formulation was decreased. The
hardness of the tablets of all formulations ranged from 3.00 ±
0.06 to 7.50 ± 0.02 kg/cm2. In weight variation test, the phar-
macopoeial limit for the percentage deviation for the tablets of
more than 250 mg is ± 5%. The average percentage deviation
of all tablet formulations was found to be within the above
limit and hence all formulations were passed the test for uni-
formity of weight as per official requirement. The content uni-
formity in the prepared tablets reflects that the method adopted
for preparation is acceptably good.
Among the formulations, the release rate increased lin-
early with increasing viscosity grades. These polymers have
been well known to retard the drug release by swelling in aque-
ous media. SodiumCMC released the drug at faster rate than

Vol. 2, Issue-1, JAN-JUNE, 2009 -19-


did HPMC at the same drug and polymer ratio. A polymer’s
ability to retard the drug release rate was dependent on its
viscosity grade (Raymond et al 2006). The faster dissolution
rate observed in sodiumCMC could be due to disintegration
property of sodiumCMC along with swellability. The HPMC,
which is mixed alkyl hydoxyalkyl cellulose ether containing
methoxy and hydroxypropyl groups, can potentially retard
the release upto 24 h, and was selected for formulation. The
hydration rate of HPMC depends on the nature of these sub-
stituents and increases specifically with an increase in the
hydroxypropyl content. The ethyl cellulose (EC) controlled
the drug release in a better manner; which could be attributed
to the decreased penetration of the solvent molecules in the
presence of hydrophobic polymer and leading to decreased
diffusion of the drug from the matrix. From commercial point
of view, EC is more economic because it was used in small
quantity. Hence F6 emerged as the most successful formula-
tion, which utilized the approach of non-aqueous granulation
using hydrophobic polymer EC with respect to retardment of
the release and cost effectiveness.
5. CONCLUSION:
Matrix tablets could be prepared by compressing the
granules formulated and these have shown acceptable phar-
maceutical characteristics and better release profile when com-
pared to the marketed brands. The formulation F6 given drug
release extended up to 24 hours with no initial burst up fol-
lowing zero order release kinetics. The drug and HPMC in
1:4 ratio and ethyl cellulose as granulating agent is proven to
be a successful approach to sustain the drug release in matrix
tablets.
Acknowledgement:
The part of this work was presented in the 1st IAPST Inter-
national Conference on Drug Delivery and Drug Targeting
Research held at Jadavpur University, Kolkata.
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