^{1 INTRODUCTION}^:

^{Oral Solid dosage
forms are some of the most popular and convenient methods of drug delivery.
They can be produced in a non-sterile environment and the process, equipment
and technology is well defined and known, after more than 100 years of
development.}

^{With the high volume of products produced in these dosage
forms, it is important that the unit operations for their production be
thoroughly understood, developed and implemented. This course focuses on the
fundamentals of each discrete processing step (unit operation) with extensive
discussions on the current technologies required for the manufacturing and
packaging of tablets and capsules [1-5]. The course uses a Process and
Production Simulation for Unit Operations including Mixing, Blending, Drying,
Sizing, Tableting, Encapsulation and Coating to provide participants with a
demonstration of current manufacturing and engineering practices.
Troubleshooting through video simulation will vividly provide real-time
experiences for identifying the problem, analyzing the problem and solving the
problem [6-13].}

^{Drug Profile:}

^{Aceclofenac Sodium}

^Description:

^{Aceclofenac is a non-steroidal anti-inflammatory
drug (NSAID) analog of Diclofenac. It is used for the relief of pain
and inflammation in rheumatoid arthritis, osteoarthritis and ankylosing spondylitis
and mild to moderate pain. The dose is 100 mg twice daily. It should not
be given to people with porphyria or
breast-feeding mothers, and is not recommended for children. Aceclofenac has
higher anti-inflammatory action than conventional NSAIDs. It is a cytokine inhibitor. Aceclofenac works by
blocking the action of a substance in the body called cyclo-oxygenase.
Cyclo-oxygenase is involved in the production of prostaglandins (chemicals in the body) which
cause pain, swelling and inflammation. Aceclofenac is the glycolic acid ester of Diclofenac[6-13].}

^Structure:

^{IUPAC Name:}

^{2-[2-[2-[(2, 6-dichlorophenyl) amino]
phenyl] acetyl] oxyacetic acid.}

^{Emperical Formula:}^{C16-H13-Cl2-N-O4}

^{Molecular
Weight}^:^354g/mol

^{Chemical Name:}^{Glycolic acid, [o-(2,6-dichloroanilino) phenyl] acetate
(ester)}

^Characters^{: Appearance}

^{White or almost white, crystalline powder.}

^Solubility:

^{Practically insoluble in water, freely soluble in
acetone, soluble in alcohol.}

^{Melting point:}^149-153°C

^{Pharmacokinetics:}

^{Aceclofenac is a phenylacetic acid
derivative that inhibits synthesis of the inflammatory cytokines interleukin-1b
and tumour necrosis factor, and inhibits prostaglandin E2 production. It
increases glycosaminoglycans (GAG) synthesis, the principal macromolecule of
the extracellular matrix, which aids in repair and regeneration of articular
cartilage. Thus, aceclofenac has positive effects on cartilage anabolism
combined with modulating effect of matrix catabolism. [14]}

^{2 MATERIALS AND METHODS:}

^{The objective of the study is to
formulate and evaluate controlled release pellets of Aceclofenac sodium which
was used as a model drug}^{through pellitization technique by using the blend of Sodium alginate
(SA) and Glyceryl palmito stearate (GPS) as hydrophilic and hydrophobic
carriers, along with Methyl crystalline cellulose (MCC) as spheronizer enhancer
in various concentrations and examines the influences of various process
parameters of drug containing pellets. Primary objective of the work is to
improve bio-availabilty,to reduce dosing frequency through control released systems
of Aceclofenac sodium pellets [14-15]. In recent years a wide variety of newer
oral drug delivery systems like controlled/sustained release dosage forms are
designed and evaluated in order to overcome the limitations of conventional
therapy. These products are able to maintain steady drug plasma levels for
extended periods of time as a result the variations of the drug levels in the
blood are prevented and minimized drug related side effects. To achieve maximum
therapeutic effect with a low risk of adverse effects, controlled released
preparations are preferred. The side effects could be lowered by controlling
the drug release and by adjusting the absorption rate. This can be achieved by
employing suitable modifications in the manufacturing process [16].}

^{Individual objectives to be attained are: -}

¹⁾^{Preformulation
studies}

²⁾^{Preparation
of pellets}

³⁾^{Compression
of pellets}

⁴⁾^{Study of
post compression parameters like angle of repose,}^{co-efficient,}^{drug content and in-vitro drug release.}

⁵⁾^{Stability
studies.}

^MATERIALS:

^{List of
Materials}

^S.NO	^{Chemicals used}	^Supplier
¹	^{Aceclofenac sodium} ^{(gift sample)}	^{Dr. Reddy’s laboratories Hyderabad}
²	^{Sodium alginate}	^{Research Lab Fine Chem Industries, Mumbai}
³	^{Micro crystalline cellulose}	^{Research Lab Fine Chem Industries, Mumbai}
⁴	^{Sodium lauryl sulphate}	^{Research Lab Fine Chem Industries, Mumbai}

^{List of
Equipments}

^S.NO	^{Equipments used}	^Manufacturer
¹	^{UV spectrophotometer}	^{SHIMADZU 1800 corporation}
²	^{FT-IR spectrophotometer}	^{SHIMADZU 8033, USA}
³	^{PH meter}	^{EI PH meter}
⁴	^{Dissolution apparatus}	^{USP XXI dissolution apparatus}
⁵	^{Particle size}	^{Optical Microscope}
⁶	^{Scanning electron microscopy analysis}	^{Scanning Electron Microscopy (model-LV 5600, jeol,USA)}
⁷	^DSC	^{2010 DSC module}

^METHODS:

^{Preformulation
studies:}

^{Preformulation was the first step in rational
development of dosage forms of a drug substance. It can be defined as an
investigation of physical and chemical properties of a drug substance alone and
when combined with excipients.}

^{Particle size analysis}

^{The particle sizes of drug loaded
formulations were measured by an optical microscope fitted with an ocular and
stage micrometer and particle size distribution was calculated. The Olympus
model (SZX-12) having resolution of 40x was used for this purpose. The
instrument was calibrated at 1 unit of eyepiece micrometer was equal to 1/30mm
(33.33μm). In all measurements, at least 20 particles in five different
fields were studied. Each experiment was carried out in triplicate.}

^{Measurement of
micromeritic properties:}

^{Angle of repose (θ) was assessed to
know the flowability of matrix pellets, by a fixed funnel method using the
formula; tan (θ) = height / radius (1)}

^{Tap density and bulk density of the pellets
were determined using tap density tester. The percentage Carr’s index (I, %)
was calculated using the formula;}

^{Carr’s index (I, %) = Tapped density – Bulk
density/Tapped density (2)}

^{Granule density of the pellets was
determined by displacement method using petroleum ether.}

^{Granule density = Weight of pellets/Volume
of petroleum ether displaced (3)}

^{The Hausner’s ratio of the matrix pellets
was calculated using the formula;}

^{Hausner’s ratio = Tapped density / Bulk
density (4)}

^{The friability test was performed on the
pellets to ensure their mechanical strength. Lower friability values indicate
good mechanical strength. Pellets of known mass (1000 – 1400 m) were placed in
a Roche Friability tester (Electro lab Friability tester, EF -2) and subjected
to impact testing at 25 RPM for 5 min. Pass the pellets through a sieve of mesh
size 16 (1000μm), weight of pellets retained on the sieve was noted and
the friability was calculated using the following equation;}

^{Friability (%) = [1– initial weight /
weight retained after 100 rotations] × 100 (5)}

^{Scanning electron
microscopy analysis (SEM):}

^{The shape and surface characteristics were
determined by scanning electron microscopy (model-LV 5600, jeol, USA and
photomicrographs were recorded, by suitable magnification at room temperature.
In order to determine the sphericity of the pellets, the tracings of pellets
(magnification 45 X) were taken on a block paper using Camera Lucida (model
-Prism type, Rolex, India) and circulatory factor was calculated using the
equation;}

^{S = p2 / (12.56 X A) (6)}

^Where,

^{A is the area (cm2) and p is the perimeter (cm)}

^{Differential scanning
calorimetry (DSC):}

^{DSC studies were carried out to study the thermal
behaviors of drug alone and mixture of drug and polymer using Du Pont thermal
analyzer with 2010 DSC module. Calorimetric measurements were made with the
help of an empty cell (high purity alpha alumina disc) as the reference. The
instrument was calibrated using high purity indium metal as standard. The DSC
scans of the samples were recorded in the temperature range ambient to 156° C
in nitrogen atmosphere at a heating rate of 10° C /min}^[16-18]^.

^{Fourier transform-
infrared spectroscopic analysis (FT- IR):}

^{Drug polymer interactions were studied by
FT-IR spectrophotometer (Shimadzu, 8033, USA) by KBr pellet method. The IR-
spectrum of the pellet from 450- 4000cm-1 was recorded.}

^{Determination of
drug content:}

^{For determination of drug content, 100 mg
pelletss were dissolved in 100 ml of methanol. The resulted solution was
analyzed spectrophotometrically at 274 nm (Shimadzu-1601, Japan) after suitable
dilution with phosphate buffer (pH 7.4) [19-21].}

^{Loose surface
crystal study (LSC):}

^{This study was conducted to estimate the
amount of drug present on the surface of the pellets and 100mg of pellets were
suspended in 100ml of phosphate buffer (pH 7.4). The samples were shaken
vigorously for 15min in a mechanical shaker. The amount of drug leached out
from the surface was analyzed spectrophotometrically at 274 nm; percentage of
drug released with respect to entrapped drug in the sample was recorded.}

^{In vitro drug
release studies:}

^{USP XXI dissolution apparatus, type II was
employed to study the percentage of drug release from various formulations
prepared [22]. Accurately weighed quantities of drug (Aceclofenac - 100 mg
equivalent to a commercial preparation – Aceton SR– 100 mg tablet) and drug
loaded pellets of each batch were taken in 900 ml dissolution medium and drug
release was studied (Aceclofenac – 2 hrs in pH 1.2, hydrochloric acid buffer
and 6 hrs in pH 7.4, phosphate buffer) at 100 rpm and at a temperature of 37 ±
0.5 °C. 10 ml of dissolution medium was withdrawn periodically using guarded
sample collectors at regular intervals (30 min for first 4 h and at 60 min
intervals for the next 20 h), the sample (10 ml) was withdrawn and replaced
with same volume of fresh medium.}

^{The withdraw sample were filtered through a
0.45μm membrane filter and after appropriate dilution using guarded sample
collectors, then estimated for ACS concentration spectrophotometrically. The
release data was analyzed using PCP dissolution - V2 – 08 and Graph Pad Instat
software. The data, thus obtained was fit into Peppas model. The various
parameters the intercept A, the release constant K and regression coefficient
R2 were calculated. Where, f1 - differential factor, f2 - similarity factor, n
– number of time point, Rt –dissolution value of the reference at time, ‘t’ and
Tt - dissolution value of test formulation at time ‘t’. Differential factor, f1
was calculated by the percentage difference between the two curves at each time
point and measured the relative error between the two curves. The acceptable
range for differential factor, f1 is 0 -15. The similarity factor, f2 was
logarithmic reciprocal square root transformation of the sum-squared error and
is a measure of the similarity in the percentage dissolution between the
reference and test products. If dissolution profile to be considered similar,
the values for f2 should be in the range 50 – 100}^[22-23]^.

^{Stability studies
of pellets:}

^{After determining the drug content, the
optimized drug contain pellets were charged for the accelerated stability
studies according ICH guidelines. To assess stability, accurately weighed drug
contain pellets equivalent to 100mg of Aceclofenac sodium were filled into a
hard gelatin capsules manually and sealed in a aluminum packaging coated inside
with polyethylene. The studies were performed at 40 ± 20° C and 75 ± 5%
relative humidity (RH) in the desiccators with saturated salt solution for up
to 90 days. A visual inspection and drug content estimation was conducted every
15 days for the entire period of stability study. Drug content was estimated
spectrophotometrically at 274 nm.}

^{PREPARATION OF PELLETS:}

^{The pellets were prepared by pelletization
technique using extrusion /spheronization method. ACS, SA, GPS and MCC were
passed through sieve No. 40 prior to pelletization and mixed uniformly in a
planetary mixer. The buble free SLS 80 (0.3 %) solution was added dropwise to
the the mixture and mixed for 30 min. The obtained good dough mass was extruded
using a piston extruder (1 mm orifice, Kalweka, India). The extrudates were
immediately spheronized for 5 min at a rotational speed of 750 rpm and an air
velocity of 1 kg/cm2. The pellets were dried over night at room temperature and
cured at 40° C for 24 h in a fluid bed dryer (Kothari, India). Five batches of
drug loaded pellets were prepared to investigate the effect of certain
formulation and process variables, such as drug to blend of polymer ratio,
concentration pore forming agent, spheronization speed and time on the mean
particle size, yield and in-vitro drug release [24-25].}

^{FORMULATIONS:}

^{In the present study, MCC posses a good
extrusion aid at optimal concentrations of 55 %, influences the mean diameter
of the pellets. Due to good binding properties of MCC, it provides cohesiveness
to a wetted mass, able to retain a large quantity of binding agent helps to
provide large surface area [24-25]. Hence the optimal concentrations of MCC
also improves the plasticity of wetted mass and enhancing spheronization by
preventing phase separation, during extrusion spheronization was observed. A
similar optimal concentration of MCC was reported [25].}

^{3
RESULTS AND DISCUSSIONS:}

^{COMPATIBILITY STUDIES:}

^{The IR spectra of the ACS and drug contain
pellets (formulation F5) were found to be identical and presented. The FTIR
spectra of the pure drug and formulation F5 indicated that characteristics
bands of ACS were not altered without any change in their position after
successful encapsulation, indicating no chemical interactions between the drug
and carriers used.}

^{DSC scans were recorded for ACS and
formulation (F5). A representative thermogram of the ACS and optimized
formulation (F5) is shown in Figure 3. The pure ACS displayed a single sharp
endothermic peak at 155.41° C corresponding to the melting point of the drug
and identical peak was observed at 155.41° C in the ACS formulation (F5). This
result clearly indicated that the drug retains its identity in the formulation
(F5). The additional peak in the formulation (F5) in the DSC thermograms was
noticed. This is an agreement with literature findings [24].}

^{Figure 1:
FTIR Spectra of pure drug and optimized formulation (F5)}

^{IN-VITRO DRUG RELEASE:}

^{In vitro}^{release studies were carried out for the
formulations in both acidic and basic media to stimulate}^{in vivo}^{conditions. Drug release profile from
pellets was a biphasic manner, consisting of initial fast release followed by a
slow release. This result could be attributed to the dissolution of the drug
present initially at the surface of the pellets and rapid penetration of
dissolution media from the matrix structure. The higher amount of ACS released
was observed from formulation F5 (96.23%) as compared to all other formulations
F1 (85.34 %), F2 (86.23 %), F3 (87.98%) and F4 (88.78 %). This result clearly
indicates that lowered drug release was noticed for the systems containing
higher content of SA. Because higher water swellable SA particles forms higher
viscosity, retards the penetration of dissolution media into pellets, thus
limiting the drug release from pellets. This typical behavior was commonly
observed in diffusion controlled drug delivery systems [24].}

^{Figure 2: DSC thermograms of pure drug and Optimized
formulation (F5)}

^{The drug release profile obtained for
formulation F5 indicated that it is an ideal formulation for administration for
every 24 h, as it released 96 % of the embedded drug in 24 h. In this
investigation author made an attempt to prepare the pellets with lower levels
of SA and higher concentrations of aqueous SLS solution (0.9 % w/w), pellets
exhibited initial burst release of drug. This result could be attributed to the
dissolution of drug present initially at surface of the matrices and rapid
penetration of dissolution media into pellets matrix structure. However, the
formulations exhibited little burst effect at higher levels of SA. Further
increased SA amount, formed thicker gel around the pellets, strongly inhibiting
the dissolution media penetration, resulting in significant reduction in the
drug release. This finding indicated a considerable release retarding potential
of the drug from pellets by varying ratios of SA / GPS /MCC and pore former.
The effect of curing of pellets at different temperature ACS release from SA
/GPS/ MCC pellets was studied. Interestingly pellets cured at 400° C for 24 h
showed controlled drug release. Drug release upon curing at 400° C (24 h) might
be due to residual moisture content present in the pellets. This result
indicates that the moisture present in the pellets reduces the cohesive force,
which facilitates the wetting of pellets and increased the pellets
disintegration (confirmed visually). Pellets cured above 450° C for 24 h,
showed the least drug release, due to least amount of residual moisture content
present in the pellets responsible for low wettability. Drug contain pellets
are softened and produced a denser structure, less permeable for dissolution
media, delayed the disintegration of pellets (confirmed by visual observation).
This result clearly indicates drug delivery from SA/GPS/MCC pellets depends on
curing conditions and moisture content. To better understand the morphology of
the pellets and potential changes occur after exposure to the release media was
observed by microscopy. Fig.4 shows photographs of ACS loaded pellets before
and after 2 h exposure to 0.1N HCl and phosphate buffer pH 7.4 respectively. It
is evident that the pellets were initially spherical in shape and there was no
change occurred up to 30 min exposure. But pellets started to looses their
edges slowly by disintegration after exposed to 0.1N HCl for 2 h. When pellets
exposed to phosphate buffer pH 7.4 (after 2h), the edges of the pellets start
to disintegrate rapidly and resulting in drug release.}

^{Figure 3: Percent drug release profile of
ACS from optimized formulation (F5) and Aceton SR}^{100 mg tablet in the gastric and intestinal environment
against the time. F5 and Aceton SR}^{100 mg tablet.}

^{RESULTS AND DISCUSSIONS:}

^{Evidence have shown in the recent years
that lipidic materials have the physical properties and behavior suitable to
prepare matrix pellets to release the entrapped drug into gastro intestinal
tract [19,22].}

^{In the present study, blend of SA, GPS and
MCC formulated as pellets by different ratio using non-toxic solvent, presented
in Table 1. The present method is quite different from that reported by Siepman
et al [23], because, none of them succeeded to formulate pellets by
blend of SA, GPS and MCC by extrusion– spheronization technique. In the present
study, examines influences of various process parameters on physicochemical
properties and drug release potential from pellets have been studied.
Incorporation of drug into different ratios of SA blend affects the physical
appearance of the pellets was observed.}

^{In the present study the formulation F5
having the optimum drug and SA blend ratio (30: 10: 05: 55) suitable to produce
solid, discrete, spherical, free flowing pellets and having a sufficient
mechanical strength. Resultant pellets did not have any surface irregularities
and they are non-aggregated. It was found that the higher the ratio of drug
used (30, 40 and 50 % w/w) SA blend were produced aggregate pellets masses
during spheronization and resulted pellets were unsuitable for pharmaceutical
uses. SEM photographs also indicated the presence of the drug crystals on the
surface of the pellets. Because surface accumulated drug resulting in burst
release and impossible to control the drug release from the pellets during
dissolution. In the present study, optimized ratio of 10 % w/w of SA was used
to produce spherical pellets. It was found that higher ratio of SA (> 10 %
w/w) or decreased ratio of SA (< 10 % w/w), the produced pellets were not
spherical and impossible to distinguish as individual pellets. In order to
avoid the formation of irregular shaped pellets, an optimum of 10 % w/w ratio
was used to prepare pellets.}

^{To obtain optimal concentrations of GPS,
concentrations ranging from 1 to 5 % w/w of the total formulations were
investigated. In the present study, optimum concentration, 5% w/w of GPS was
used to produce better pellets. In order to obtain optimal concentrations of
pore forming agent, various concentrations of aqueous solution SLS ranging from
0.1 to 1.0 % w/w of the total formulations were investigated. But 0.1 to 0.5 %
of aqueous solution SLS failed to produce required pores in the pellets. When
more than 0.6 % w/w aqueous solution SLS was used, resultant pellets contains
sufficient numbers of pores. In the present study, optimum concentration, 0.6 %
w/w of aqueous solution SLS was used as pore forming agent in the pellets.
Incorporation of hydrophilic (SA) into lipophilic (GPS) polymer requires the
addition of wetting agent at an optimum concentration of aqueous solution of
SLS (9 ml of 0.6 % w/w) to reduce the interfacial tension between SA and GPS.
An attempt was made to prepare wet mass without the addition of wetting agent.
But the process was failed and as it resulted, in an aggregate cake like mass
during the pelletization. It may due to repulsion resulting between GPS and
MCC. It was found that hydrophilic and lipophilic balance (HLB) value of SLS is
40, found to be more suitable to increase substantial dispersion of drug in SA
blend. It was also noticed that 9 ml of aqueous solution of SLS (0.6 % w/v) was
used as wetting agent, produced pellets were spherical, free flowing, free from
surface irregularities. As the volume of aqueous solution of SLS was more than
9 ml, resultant pellets were sticky, aggregate, and impossible to produce s
spherical shaped pellets.}

^{As the volume of the aqueous solution of
SLS was less than 9 ml, requires more pressure for pelletization and difficult
to separate as an individual pellets. Hence, the changes in volume of SLS solution
as wetting agent affects the the sphericity of the pellets, was confirmed by
SEM photographs (Fig. 4 a). The important factor that influences the size
distribution of pellets was the spheronization speed and residence time. A
spheronization speed of 200 rpm and residence time 6 min was used to obtain
reproducible and uniform sized pellets. As increase in spheronization speed
from 50 to 200 rpm, a change in the shape and size of the pellets were noticed.
When the spheronization speed was 50,100, 150 rpm produces rod, egg and semi
spherical shaped pellets respectively. Increased spheronization speed from 200
to 300 rpm, a reduction in the average sizes and recovery yield of the pellets
was observed. Spheronization speed was lower than 200 rpm, larger and irregular
shaped pellets were formed and not suitable for pharmaceutical purpose.}

^{It was found that 200rpm was optimized
condition to produce discrete, spherical, hard and free flowing solid pellets.
Spheronization time also affects on the pellet shape and size (Table 1). It was
also found that an increase in spheronization residence time from 3 to 6 min
(at a stirring speed of 200 rpm) resulted in changes in the shape and size of
the pellets. From the study, optimized spheronization time was found to be 5
min, suitable to produce spherical, hard and free flowing solid pellets.}

^{However, further increases in
spheronization time considerably affect the pellet shape and size. Hence, to
produce required shape and sizes of the pellets, optimum spheronization speed
(200 rpm) and spheronization residence time (6 min) was used. In the present
study, MCC posses a good extrusion aid at optimal concentrations of 55 %,
influences the mean diameter of the pellets. Due to good binding properties of
MCC, it provides cohesiveness to a wetted mass, able to retain a large quantity
of binding agent helps to provide large surface area. Hence the optimal
concentrations of MCC also improves the plasticity of wetted mass and enhancing
spheronization by preventing phase separation, during extrusion spheronization
was observed. A similar optimal concentration of MCC was reported [21].}

^{The values of angle of repose (θ) for
the pellet were in the range 25.13 - 27.23 indicating good flow potential for
the pellets. The measured tapped density (0.821 to 0.896 g /cm3), granule
density (1.024 to 1.076 g/ cm3), % Carr’s index (8.45 to 9.56%), and Hausner
ratio (1.023 to 1.165), were well within the limits, which indicates good flow
potential for the prepared pellets.}

^{The friability of the ACS pellet
formulations was found to be in the range 0.39 - 0.53 % and it falls in the
expected range (less than 5% as per FDA specification). Friability is measured
to assess the mechanical strength of the pellets in terms of fragmenting or
powdering during filling operation into capsule shell. As the ratio of MCC and
GPS higher, friability of the formulation was increased (Table 2).}

^{Additionally, pellets cured at 40° C for
24h produces pellets with good mechanical strength due to low moisture content.
As the curing temperature increases (45°C for 24 h), friability of the pellets
found to decreases and pellets having shrinked porosities was observed, due to
loss of moisture content. When the pellets cured below 40° C for 24 h, produced
pellets were dumbbell shaped with protruding}^{surfaces (}^{confirmed from SEM photomicrographs}^{) and these pellets not suitable for}^{pharmaceutical purpose.}^{SEM photomicrographs (Fig.4 a), showed
that the pellets (formulation F5) were spherical in nature and had a smooth
surface when they cured at 24 h at 40° C.}

^{SEM photomicrographs of the pellets reveal
the uniform distribution of the drug in the pellets.Figure 4 (b) shows the SEM
photomicrographs of the surface of the pellets and presence of fine pores (F5).
The formed fine pores on the pellets can be clearly observed. When the pellets
were cured at 24 h for\45° C, surface inward dents and shrinkage were observed
(collapse of the wall of the pellets), which might be due to drop in residual
moisture content from pellets. The drug crystals observed on the surface as a
result of their migration along with water to the surface during drying. This
result clearly indicates that influence of moisture content on surface
morphology of the pellets [23].}

^{Figure 4: (a) SEM photomicrographs showed
that the pellets (formulation F5) were spherical in nature and had a smooth
surface}^.

^{Figure 4: (b) SEM photomicrographs showed
that the pellets (formulation F5) were with fine pores and had a porous rough
spherical surface}^.

^{Drug content in all the formulations were in the range
of 97.42 - 96. 89 % w/w. Drug content was least in formulation F1 (96.89 %
w/w/) and high for formulation F5 (97.42 % w/w/). It is evident that, the drug
content increases with increased in pellets size (1024 to1212 m). This might be
due to increased relative surface area of the pellets, leads to more drug
content.}

^{Loose surface crystal (LSC) study was an important
parameter to know the amount of drug deposited on the surface of the pellets
without proper distribution. With increasing concentrations of SA, LSC
decreased significantly.}

^{In vitro release studies were carried out for the
formulations in both acidic and basic media to stimulate in vivo conditions.
Drug release profile from pellets was a biphasic manner, consisting of initial
fast release followed by a slow release. This result could be attributed to the
dissolution of the drug present initially at the surface of the pellets and
rapid penetration of dissolution media from the matrix structure. The higher
amount of ACS released was observed from formulation F5 (96.23%) as compared to
all other formulations F1 (85.34 %), F2 (86.23 %), F3 (87.98%) and F4 (88.78
%). This result clearly indicates that lowered drug release was noticed for the
systems containing higher content of SA. Because higher water swellable SA
particles forms higher viscosity, retards the penetration of dissolution media
into pellets, thus limiting the drug release from pellets. This typical
behaviour was commonly observed in diffusion controlled drug delivery systems
Differential factor (f1) and similarity (f2) factor was calculated from
dissolution profile and the results were compared to the formulation, F5 and
Aceton SR– 100 mg tablet.}

^{The differential factor (f1) and similarity factor
(f2) obtained from dissolution profile indicates that the formulation F5 (8.32,
9.03) and Aceton SR– 100 mg tablet (75.67, 76.98) were similar. The calculated
diffusivity values are given in Table 3. From the table 3; it is noticed that,
diffusivity values of trial 1 (without SA) is quite high, since there is no
barrier to control the drug release. The values of F1 and F2 are quite low, due
to fewer amounts of GPS, MCC and more amount of SA, resulted in less solubility
of drug in aqueous media. On the other hand, the diffusivity values for
formulations F3 and F4 was slightly higher. This is due to fact that more ratio
of GPS, MCC and less ratio of SA, so the drug diffuses easily into the external
environment. Formulation F5, which showed optimum drug release during the in
vitro dissolution studies, exhibited a higher diffusivity. It also supports the
fact that the drug is easily diffusible through the pores formed in the pellets
membrane.}

^{Table 3:
Diffusivity data of All SA/ GPS/ MCC Pellets.}

^Formulations	^{D1ax 109 (cm2/s)}	^{D2ax 109(cm2)}
^{Trial 1 (without GPS)}	^1.43	^1.32
^F1	^0.48	^0.38
^F2	^0.53	^0.50
^F3	^0.64	^0.62
^F4	^0.73	^0.69
^F5	^0.94	^0.88

^{The optimized formulation F5 was subjected
for accelerated stability studies. Stability studies were carried out 400 ± 10°
C and 75 % ± 5 % relative humidity for a period of 90 d .It was observed that,
no significant change in the drug content from the pellets was observed. It is
evident from the table 3 that, formulations F5 exhibited good stability during
investigation period, which indicates the drug was in stable form.}

^{Table 4: Analytical stability study results of
optimized pellets (F5) stored at 40}^{° C}^{and 75% RH.}

^{Sampling duration}^(days)a	^{Drug content}^(%)a
⁰	^97.42
¹⁵	^97.40
⁴⁵	^97.39
⁹⁰	^97.38

⁴^{SUMMARY
AND CONCLUSION:}

^{The objective of the present study was
directed towards development and evaluation of controlled release anti-inflammatory
drug aceclofenac sodium pellets to achieve controlled release of the drug.
Aceclofenac sodium pellets were used as a model drug. The prepared pellets were
evaluated for both pre-compressive and post-compressive parameters. All the
parameters were under acceptable ranges. The higher amount of ACS released was
observed from formulation F5 (96.23%) as compared to all other formulations F1
(85.34 %), F2 (86.23 %), F3 (87.98%) and F4 (88.78 %). This result clearly
indicates that lowered drug release was noticed for the systems containing
higher content of SA. Drug release profile from pellets was a biphasic manner,
consisting of initial fast release followed by a slow release. The optimized
formulation F5 was subjected for accelerated stability studies. Stability
studies were carried out 400 ± 10° C and 75 % ± 5 % relative humidity for a
period of 90 d .It was observed that, no significant change in the drug content
from the pellets was observed. It is evident from the table 3 that,
formulations F5 exhibited good stability during investigation period, which
indicates the drug was in stable form.}

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^{Received on 06.05.2017 Accepted on 09.07.2017}

^{Asian J. Pharm. Ana. 2017; 7(3)}^{: 176}^-184.

^DOI:10.5958/2231-5675.2017.00028.X

^Formulation	^{Yield (%)}	^Average ^{Size (m)}	^{Angle of repose θ}	^Tapped ^{Density (g/cm3)}	^Granule ^{Density (g/cm3)}	^Carr’s ^{Index (%)}	^Hausner ^{Ratio (%)}	^Friability ^(%)
^F1	^91.22	¹⁰²⁴	^27.23	^0.821	^1.024	^8.91	^1.023	^0.39
^F2	^92.80	¹⁰⁸⁷	^26.12	^0.854	^1.056	^8.65	^1.165	^0.42
^F3	^93.12	¹¹³⁴	^25.13	^0.828	^1.054	^8.45	^1.145	^0.45
^F4	^94.45	¹¹⁸⁹	^26.43	^0.873	^1.076	^8.78	^1.098	^0.49
^F5	^96.76	¹²¹²	^26.23	^0.896	^1.032	^9.56	^1.123	^0.53

Oral Solid dosage forms are some of the most popular and convenient methods of drug delivery. They can be produced in a non-sterile environment and the process, equipment and technology is well defined and known, after more than 100 years of development.

Molecular Weight: 354g/mol

Chemical Name: Glycolic acid, [o-(2,6-dichloroanilino) phenyl] acetate (ester)

^{Oral Solid dosage
forms are some of the most popular and convenient methods of drug delivery.
They can be produced in a non-sterile environment and the process, equipment
and technology is well defined and known, after more than 100 years of
development.}

^{Molecular
Weight}^:^354g/mol

^{Chemical Name:}^{Glycolic acid, [o-(2,6-dichloroanilino) phenyl] acetate
(ester)}