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Pellets are well accepted technique to control the drug release from the dosage form to improve bioavailability, reduce absorption difference in patients, reduce the dosing frequency and adverse effects during prolong treatment. The main objective of the present study is to prepare and evaluate controlled release pellets of Ketoprofen by extrusion sheronization method, with release rate retarding polymers using as carrier for oral administration in view to achieve oral controlled release of the drug and to protect the gastric mucous membrane from drug irritation. Ketoprofen is potent NSAID having anti-inflammatory, analgesic, antipyretic properties. It is readily absorbed from the gastrointestinal tract and peak plasma concentrations occur about 0.5–2 h after a dose, but it causes a certain irritation in the gastrointestinal mucous membrane and possesses a bitter taste and aftertaste. The half-life in plasma is about 2–3 hr. Preformulation studies performed were comply with the standards. Compatibility studies revealed there was no interaction between the drug and polymers. The various evaluation parameters were given the positive results. In-vitro dissolution studies were showed that the release of drug from pellets was optimum. It was also observed that drug release increases sharply as well as the release best fit to the zero order release kinetics.All the pellets were stable with respective storage condition.
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ISSN No: 2321 – 8630, V – 1, I – 1, 2014 Journal Club for Pharmaceutical Sciences (JCPS)
Manuscript No: JCPS/RES/2014/16, Received on: 03/08/2014, Revised on: 09/08/2014, Accepted On: 13/08/2014
RESEARCH ARTICLE
© All Rights Reserved by “Journals Club & Co.” 87
Preparation and Evaluation of Controlled Release Matrix Pellets of Ketoprofen
Patel DY*1, Joshi DM1, Shah AD1 1A.P.M.C. College of Pharmaceutical Education and Research,
Motipura, Himatnagar Gujarat, India.
ABSTRACT
Pellets are well accepted technique to control the drug release from the dosage form to improve bioavailability, reduce absorption difference in patients, reduce the dosing frequency and adverse effects during prolong treatment. The main objective of the present study is to prepare and evaluate controlled release pellets of Ketoprofen by extrusion sheronization method, with release rate retarding polymers using as carrier for oral administration in view to achieve oral controlled release of the drug and to protect the gastric mucous membrane from drug irritation. Ketoprofen is potent NSAID having anti-inflammatory, analgesic, antipyretic properties. It is readily absorbed from the gastrointestinal tract and peak plasma concentrations occur about 0.5–2 h after a dose, but it causes a certain irritation in the gastrointestinal mucous membrane and possesses a bitter taste and aftertaste. The half-life in plasma is about 2–3 hr. Preformulation studies performed were comply with the standards. Compatibility studies revealed there was no interaction between the drug and polymers. The various evaluation parameters were given the positive results. In-vitro dissolution studies were showed that the release of drug from pellets was optimum. It was also observed that drug release increases sharply as well as the release best fit to the zero order release kinetics.All the pellets were stable with respective storage condition.
KEYWORDS
Controlled release, Sodium alginate, Ethyl cellulose, Pellets
INTRODUCTION
Controlled drug delivery systems designed
to deliver drug at predetermined rates for
predefined periods of time and have been
used to overcome the shortcoming of
conventional drug formulations. The term
pellets describes a monolithic spherical
structure with the drug or therapeutic agent
distributed throughout the matrix either as a
molecular dispersion or as a dispersion of
particles (in the 700 - 1200μm size ranges)
for use as carries of drugs and other
therapeutic agents1. Ketoprofen is readily
*Address for Correspondence:
Yogesh D. Patel, Pharmaceutics Department, A.P.M.C. College of Pharmaceutical Education and Research, Motipura, Himatnagar – 383001, Gujarat, India Email: [email protected]
All Rights Reserved by “Journals Club & Co.” 88
absorbed from the gastrointestinal tract and
peak plasma concentrations occur about
0.5–2 h after a dose, but it causes a certain
irritation in the gastrointestinal mucous
membrane and possesses a bitter taste and
aftertaste.2 The half-life in plasma is about
2–3 hr. The short half-life and the low
single administration dose make ketoprofen
a very good candidate for the formulation
of controlled release dosage forms. The
main objective of the present study was to
prepare and evaluate controlled release
pellets of ketoprofen by extrusion
sheronization method, with release rate
retarding polymers, such as ethyl cellulose
and sodium alginate using as carrier for oral
administration in view to achieve oral
controlled release of the drug and to protect
the gastric mucous membrane from drug
irritation or to mask its unpleasant taste.3
The pellet dosage form can be prepared as a
capsule or tablet. Formulation of drug into
pellet form may reduce gastric irritation as
well as gastrointestinal side effects, because
the drug is released slowly over a period of
time, therefore avoiding high drug
concentration in the stomach. Pellet dosage
form also allows drug to be absorbed
gradually, therefore reducing the incidence
of side effects by preventing high Cmax. A
major advantage of pellet dosage form is
that the pellets are less sensitive to the
effect of stomach emptying. Because there
are numerous pellets within a capsule, some
pellets will gradually reach the small
intestine and deliver the drug, where as a
single tablet may be delayed in the stomach
for a long time due to erratic stomach
emptying. The fluctuating drug
concentrations in blood and tissues caused
by conventional dosage forms lead to an
insufficient influence on the mechanisms of
disease and are related to the excessive use
of a drug.2
MATERIALS & METHODS
Materials
Ketoprofen was obtained from Torrent
pharma, Ahmedabad,Gujarat, India as gift
sample. It is insoluble in water; soluble in
alcohol and methyl alcohol. Micro
crystalline cellulose pH 101 (MCC) was
procured from Signet Chemicals, Mumbai,
India. It is a white colourless, odorless,
tasteless and crystalline powder.Ethyl
Cellulose was obtained from SD fine -
Chem Ltd., Mumbai, India. Sodium
alginate was obtained from SD fine -Chem
Ltd., Mumbai, India. It is a white to
yellowish brown filamentous, grainy,
granular or powdered forms of the sodium
salt of alginic acid. β-cyclodextrin was
obtained from Yarrow Chem Products,
Mumbai, India.
Preparation of Ketoprofen Inclusion
Complexation by Kneading Method
The binary system of Ketoprofen and β-
cyclodextrins in different ratios (1:1) were
All Rights Reserved by “Journals Club & Co.” 89
triturated in a mortar with a small volume
of water: ethanol (1:1 v/v,3 ml) solvent
blend.4 The thick slurry was kneaded for 45
mins, and then the mass was dried in for
2 days. The dried product was crushed,
pulverized and sieved through 100 mesh.5
The solid dispersions thus obtained were
stored in a well-closed container. Solubility
study and drug content test were carried
out.7
Evaluation of Ketoprofen-βcyclodextrin Inclusion Complexation Solubility study6 Solubility study was carried out by taking solid dispersion in 3 ml of phosphate buffer pH 7.4 and distilled water, sonicated for one hour and maintained at temperature 37º for 72 h. The content of ketoprofen was determined spectrophotometrically at 256 nm. Drug content6 Solid dispersion equivalent to 100 mg of drug was weighed, transferred in to a flask (100 ml) and first dissolved in 10 mL of solvent methanol and then make up the volume up to 100 mL with 7.4 pH buffer
solution. The solution filtered through 0.45μ filters was measured using UV-Visible spectrophotometer at 260nm (λmax). To avoid the interference of the excipients, placebo blend was also treated similarly and kept as blank. Preparation of Pellets8 Extrusion-Spheronization process used for pellets preparation. Accurately weighed amount of drug, microcrystalline cellulose, sodium alginate and ethyl cellulose were mixed in the mortar-pastel. Solvent water was used for the wet massing to make the dump mass of optimum moisture content. Then this mass was kept in extruder for getting extrudes. The wet extrudes were placed in an oven for optimum % LOD (Loss on drying). If there was higher moisture then extrudes stick with each other and if it was less then there were chances of fine particles. After this stage extrudes were placed in spheronizer for getting sphere pellets. The prepared spherical pellets were placed in hot air oven to dry for 30 minutes. Composition of F1 to F9 batches prepared by trial and error method show in table 1 and 2.
Table 1 : Composition of Drug and Excipients of F1 to F5
Ingredients F1
(mg)
F2
(mg)
F3
(mg)
F4
(mg)
F5
(mg)
Ketoprofen
inclusion complex
200 200 200 200 200
Microcrystalline
cellulose
267.50 240.02 212.52 240.02 212.52
Sodium alginate 55 82.5 110 55 82.5
Ethyl cellulose 27.5 27.5 27.5 55 55
Total weight(mg) 550 550 550 550 550
All Rights Reserved by “Journals Club & Co.” 90
Table 2 : Composition of drug and Excipients of F6 to F9
Ingredients F6
(mg)
F7
(mg)
F8
(mg)
F9
(mg)
Ketoprofen inclusion
complex
200 200 200 200
Microcrystalline
cellulose
185.02 185.02 157.52 130.02
Sodium alginate 110 55 82.5 110
Ethyl cellulose 55 82.5 82.5 82.5
Total weight(mg) 550 550 550 550
Characterization and Evaluation of
Pellets
Bulk density9
Weigh accurately 25 g of powder mixture
(M), which was previously passed through
20 # sieve and transferred in 100 ml
graduated cylinder. Carefully level the
powder without compacting, and read the
unsettled apparent volume (V0). Calculate
the apparent bulk density in gm/ml by the
following formula
Bulk density = Weight of powder / Bulk
volume ……………(1)
Tapped density9
Weigh accurately 25 g of powder mixture,
which was previously passed through 20 #
sieve and transfer in 100 ml graduated
cylinder. Then mechanically tap the
cylinder containing the sample by raising
the cylinder and allowing it to drop under
its own weight using mechanically tapped
density tester that provides a fixed drop of
14± 2 mm at a nominal rate of 300 drops
per minute. Tap the cylinder for 500 times
initially and measure the tapped volume to
the nearest graduated units, repeat the
tapping an additional 750 times and
measure the tapped volume to the nearest
graduated units. Calculate the tapped bulk
density in gm/ml by the following
formula: Tapped density = Weight
of powder / Tapped ……..(2)
Carr’s Index10
The compressibility index of the powder
mixture was determined by Carr‟s
compressibility index. It is a simple test to
evaluate the BD and TD of a powder and
the rate at which it packed down. The
formula for Carr’s index is as below:
Carr’s index (%) = [(TD-BD) x100]/TD
……………….(3)
All Rights Reserved by “Journals Club & Co.” 91
Hausner’s Ratio10
The Hausner’s ratio is a number that is
correlated to the flow ability of a powder
or granular material.
Hausner’s ratio = TD / BD
……………….(4)
Angle of Repose11
The angle of repose of powder mixture
was determined by the funnel method. The
accurately weight powder blend were
taken in the funnel. The height of the
funnel was adjusted in such a way the tip
of the funnel just touched the apex of the
powder blend. The powder blend was
allowed to flow through the funnel freely
on to the surface. The diameter of the
powder cone was measured and angle of
repose was calculated using the following
equation.
tanФ=h/r …(5)
Where, h and r are the height and radius of
the powder cone respectively.
Drug Content Analysis
To determine the drug content, weight of
the crushed pellets equivalent to 100 mg of
drug was weighed, transferred in to a flask
(100 ml) and first dissolved in 10 mL of
solvent methanol12 and then make up the
volume up to 100 mL with 0.1 N HCl. The
solution filtered through 0.45μ filters was
measured using UV-Visible
spectrophotometer at 256nm (λmax). To
avoid the interference of the excipients,
placebo blend was also treated similarly
and kept as blank. Standard solution was
prepared by weighing accurately 100 mg
of Ketoprofen separately and following the
similar dilution procedure. From the
absorbance of the test solution, the amount
of drug in the solution was calculated.
In vitro Drug Release
The in vitro drug release study was carried
out using USP dissolution test apparatus 2
(paddle method). The dissolution test was
performed in 900 ml of 0.1N HCl
maintained at 37±0.5 °C for two hour at a
paddle speed of 50 rpm. A sample (10 ml)
of the solution was withdrawn from the
dissolution apparatus hourly, and the
samples were replaced with fresh
dissolution medium. The samples were
filtered through 0.45 µ membrane filter
and diluted to a suitable concentration with
respective media. Absorbance of these
solutions was measured at λmax of the
drugs in that media using double beam UV
visible spectrophotometer. Dissolution
medium was replaced with phosphate
buffer pH 6.8 after two hours for further
study.
Comparison of Dissolution Profiles for
Selection Optimum Batch
The similarity factor (f2) given by SUPAC
guidelines for a modified release dosage
All Rights Reserved by “Journals Club & Co.” 92
form was used as a basis to compare
dissolution profiles. The dissolution
profiles are considered to be similar when
f2 is between 50 and 100. The dissolution
profiles of products were compared using
an f2 which is calculated from following
formula:
………….. (7)
Where, n is the dissolution time and Rt and
Tt are the reference (here is the theoretical
dissolution profile of ketoprofen) and test
dissolution value at time t. All batches (F1
to F9) were compared with theoretical
profile for calculation of similarity factor.
Fourier Transform- Infrared
Spectroscopic Analysis (FT- IR)
FT-IR spectroscopy was carried out to
check the compatibility between drug and
polymer. The FT-IR spectra of drug with
polymers were compared with the standard
FT-IR spectrum of the pure drug.
Kinetic Modeling of Dissolution Data13,14
To analyze the in vitro release data various kinetic models were used to describe the release kinetics. The zero order rates describe the systems where the drug release rate is independent of its concentration. The first order describes the release from system where release rate is concentration dependent. Higuchi (1963) described the release of drugs from insoluble matrix as a square root of time
dependent process based on fickian diffusion. The Hixson-Crowell cube root law describes the release from systems where there is a change in surface area and diameter of particles or tablets. C=K0×t ……………………....... (8) Where, K0 = Zero-order rate constant expressed in units of concentration/time t = Time Log C = Log C0 - K1 × t / 2.303 ……………………………….….. (9) Where, C0 = Initial concentration of drug K1 = First order constant Q=KH×t1/2 ………….. (10) Where, KH = Constant reflecting the design variables of the system Q0
1/3–Qt1/3=KHC×t ………….. (11)
Where,
Qt = Amount of drug remained in time t
Q0 = Initial amount of the drug in tablet
KHC = Rate constant for Hixson-Crowell
rate equation
The following plots were made using the
in vitro drug release data
Cumulative % drug release vs. time
(Zero order kinetic model),
Log cumulative of % drug remaining
vs. time (First order kinetic model),
Cumulative % drug release vs. square
root of time (Higuchi model),
Cube root of initial concentration
minus the cube root of percentage of
drug remaining in the matrix vs. time
(Hixson-Crowell cube root law).
10011logX50 X
5.02
12
n
tttt TRwnf
All Rights Reserved by “Journals Club & Co.” 93
Kinetic study of dissolution data of
batches F6 are depicted in Table.
RESULT AND DISCUSSION
From table 3 concluded that solubility of
poorly water-soluble Ketoprofen can be
improved by using inclusion complexation
with β-cyclodextrin. This might be due to
solubilising effect of water soluble β
cyclodextrin carriers.only drug show low
solubility. By formulation of inclusion
complexation with β cyclodextrin, there
was increase solubility. At the ratio of 1:1
(Ketoprofen: β-CD) solubility of drug was
found 0.51±0.124 in water.
From table 4 result of In-vitro drug release
of batches F1 to F9 ,in F6 formulation was
found highest amount of drug release
about 98.40 % w/w. it was found that F6
batch gives drug release up to 12 hrs.
Similarity factor were calculated for all
formulations, considering theoretical
profile as the reference standard. The
values for the same are depicted in table 5.
It can be seen that formulations F1 to F4
and F7 to F9 have low f2 similarity
values(less than 50). Suggesting that these
formulation show greatest deviation from
theoretical profile as compared to other
formulated products. F5 and F6
formulations show f2 values between 50-
75 indicating low differences of
dissolution profiles with that theoretical
profile. The values of similarity factor (f2)
for the batch F6 showed maximum value
68.78. Hence, formulation batch F6 was
considered as optimize batch.
The kinetics of the dissolution data were
well fitted to zero order, first order,
Higuchi model, Hixson-Crowell and
korsmeyer-peppas model as evident from
regression coefficients.
Here F6 formulation follows zero order
release kinetics as depicted in Table 6. In
case of the controlled release formulations,
diffusion, swelling and erosion are the
three most important rate controlling
mechanisms. To find out release
mechanism the in vitro release data were
fitted in Korsmeyer-Peppas equation, the
formulations F6 showed high linearity (R2:
0.9868), with a comparatively high slope
(n) values of >0.6, which appears to
indicate a coupling of diffusion and
erosion mechanisms. Hence, diffusion
coupled with erosion might be the
mechanism for the drug release.
The FTIR spectra of drug alone and in
combination with different excipients show
that main functional group peak remain
intact in the spectrum of drug with excipient
which shows compatibility between drug
and selected excipients.
All Rights Reserved by “Journals Club & Co.” 94
Table 3 : Data of Ketoprofen- β Cyclodextrin Inclusion Complex Ratio
Ratio of
Ketoprofen: β-CD
Drug content
(%)
Solubility(mg/ml) in
water
Solubility(mg/ml) in
7.4 ph buffer sol.
Drug only 98.76±2.56 0.047±0.12 0.37±0.23
1:1 96.56±2.26 0.51±0.124 2.56±0.38
Table 4 : In-vitro Drug Release of Batches F1 to F9
Time
(hrs.)
F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 12.98 11.63 10.00 11.35 11.49 11.90 10.41 10.41 9.87 2 25.30 18.25 22.29 17.44 16.22 17.85 18.78 17.97 16.88 3 37.22 31.99 31.47 32.92 28.31 27.11 27.92 26.29 25.05 4 46.83 39.38 46.57 39.37 34.84 36.48 35.80 33.61 32.09 5 58.04 51.58 56.15 51.71 41.45 43.51 44.32 41.02 38.94 6 70.98 59.85 65.55 62.56 53.00 53.05 50.62 47.15 45.59 7 86.50 74.85 72.62 75.82 58.44 63.23 56.17 53.34 51.90 8 96.23 85.53 82.88 89.09 66.51 72.84 62.59 58.92 56.92 9 93.20 96.60 91.20 96.95 76.56 80.52 68.67 63.47 61.04
10 96.62 96.14 94.34 96.22 83.19 88.01 74.81 68.20 66.29 11 95.46 94.85 91.94 94.93 90.30 94.08 79.79 74.46 71.45 12 96.31 95.70 92.94 96.14 94.12 98.40 89.15 81.47 76.80
Table 5 : Micromeritic Characteristic of Batches F1 to F9
Batches Bulk density Tapped density
Carr’s index (%)
Hausner Ratio
Angle of repose(θ0)
F1 0.52 0.59 13.46 1.13 27.11 F2 0.57 0.61 6.55 1.07 26.35 F3 0.56 0.61 8.19 1.08 25.98 F4 0.51 0.58 12.06 1.13 28.53 F5 0.50 0.59 15.25 1.18 24.37 F6 0.56 0.60 6.67 1.07 23.05 F7 0.53 0.61 13.11 1.15 25.41 F8 0.50 0.59 10.25 1.18 29.39 F9 0.55 0.65 15.38 1.18 29.44
All Rights Reserved by “Journals Club & Co.” 95
Table 6 : Similarity Factor (f2) value for F1-F9
F1 30.46 F2 38.99 F3 39.87 F4 37.02 F5 66.28 F6 68.78 F7 47.15 F8 36.70 F9 32.80
Table 7 : Kinetic Modeling Data of F6 Batch
F6 Zero order
First Order
Higuchi Plot
Hixon Crowell
Korsmeyer
and
Peppas
R2 0.9950 0.9136 0.9792 0.9574 0.9868
Slope 8.36 0.0793 38.305 0.211 0.8503
Fig. 1 : Dissolution Profile of F1 to F9 Batches
All Rights Reserved by “Journals Club & Co.” 96
Fig. 2 : FT-IR Spectrum of the Pure Ketoprofen
Fig. 3 : FT-IR Spectra of Physical Mixture of Drug Inclusion Complex, Sodium Alginate and Ethyl Cellulose
CONCLUSION From the present study, it can be
concluded that the prepared matrix pellets
demonstrate the potential use of Sodium
alginate, MCC and ethyl cellulose blend
for the development of controlled drug
delivery systems. β-cyclodextrin , which
used as water soluble carrier for water
insoluble Ketoprofen, increased solubility
of ketoprofen. Drug inclusion
complexation was prepared by kneading
method,1:1 ratio of drug and β-
cyclodextrin optimized ratio which
increase significant solubility of drug. The
results of micromeritic properties and
hausner ratio of the pellets were well
within the limits which indicate good flow
potential for the prepared pellets. From the
FTIR studies, it was observed that there
was no chemical interaction between the
drug and polymers. The drug release rate
was found vary among the formulations
depending on the compositions of
polymers used. Formulation F6 showed
highest amount of drug release 98.40% .
Similarity factor f2 value of formulation
F6 showed 68.78 which is highest value
than other formulation batch so
formulation F6 considered as optimized
All Rights Reserved by “Journals Club & Co.” 97
batch. The n value of optimized batch,
observed by korsmeyer-peppas model was
found 0.8503, indicated that the drug
release through the polymeric matrix
follows diffusion and erosion mechanism.
Formulation F6 is an ideal formulation for
twice a day administration.
ACKNOWLEDGEMENT Authors wishes to acknowledge Torrent
pharma, Ahmedabad, Gujarat, india for
providing gift sample of drug, ketoprofen.
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HOW TO CITE THIS ARTICLE Patel, D, Y., Joshi, D, M., Shah, A, D. Preparation and Evaluation of Controlled Release Matrix Pellets of Ketoprofen. Journal Club for Pharmaceutical Sciences (JCPS), 1(I), 87-98